Further insight into the cardiovascular risk calculator: the roles of statins, revascularizations, and underascertainment in the Women's Health Study

Abstract

Importance: While the pooled cohort equations from the recent American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Assessment of Cardiovascular Risk have overestimated cardiovascular risk in multiple external cohorts, the reasons for the discrepancy are unclear.

Objective: To determine whether increased use of statins over time, incident coronary revascularization procedures, or underascertainment of vascular events explain overestimation of risk in a more contemporary population.

Design, setting, and participants: The Women's Health Study (WHS) is a nationwide cohort of US women free of cardiovascular disease, cancer, or other major illness at baseline from 1992 to 1995. A total of 27 542 women ages 45 to 79 years with complete ascertainment of plasma lipids and other risk factors were followed for a median of 10 years.

Main outcome and measure: Atherosclerotic cardiovascular disease (ASCVD), defined as any myocardial infarction, any stroke, or death due to cardiovascular cause.

Results: A total of 632 women experienced an ASCVD event over the course of the follow-up. The average predicted risk from the pooled cohort equations was 3.6% over 10 years, compared with an actual observed risk of 2.2%. Ratios of predicted to observed rates were 1.90 or higher in the groups with 0 to less than 5.0% and 5.0% to less than 7.5% risk and were over 1.40 in the groups with 7.5% to less than 10.0% and 10.0% or higher risk. Rates of statin use and revascularizations increased over follow-up time and by risk group, and in sensitivity analyses, we estimated the hypothetical rates if no women were prescribed statins or underwent revascularization procedures. After adjustment for intervention effects of statins and revascularization as well as hypothetical confounding by indication, ratios of predicted to observed rates remained 1.80 or higher in the lower 2 risk groups and over 1.30 higher in the upper 2 risk groups. Underascertainment is unlikely since follow-up rates in the WHS were 97.2%, and overall we would need approximately 60% more events to match the numbers predicted using the pooled cohort equations.

Conclusions and relevance: Statin use, revascularization procedures, and underascertainment of events do not explain the discrepancy between observed rates of ASCVD in the WHS and those predicted by the ACC/AHA pooled cohort equations. Other explanations include changing patterns of risk within more contemporary populations.

Figure 1

Observed 10-year risk of ASCVD in the Women's Health Study compared to that predicted by the ACC/AHA pooled cohort equations in clinical risk groups: A) Unadjusted; B) Accounting for a 25% reduction in ASCVD due to statin use; C) Accounting for the intervention effect (25% reduction) as well as a doubling of risk in statin users due to confounding by indication; D) Accounting for the intervention effects (25% reduction) and confounding by indication (doubling of risk) due to both statin use and revascularization procedures.

Figure 2

Calibration plot comparing observed 10-year risk of ASCVD in the Women's Health Study to that predicted by the ACC/AHA pooled cohort equations within deciles.

Figure 3

Use of medications and revascularization procedures over time in the Women's Health Study: A) Proportions using statins; B) Cumulative incidence of revascularization procedures; C) Proportions using any cholesterol-lowering medications.

Figure 4

Approximate timeline of study baseline data collection, including the derivation samples used for the pooled cohort equations (Pooled Cohort), the external validation cohorts used in the guideline report (Validation 1), and additional external cohort samples (Validation 2). * “Contemporary” cohort.