Why Risk Calculators Produce Different Answers

Editor's Note: Commentary based on Cook NR, Ridker PM. Further insight into the Cardiovascular Risk Calculator: the roles of statins, revascularizations, and underascertainment in the Women's Health Study. JAMA Intern Med 2014 Oct 6. [Epub ahead of print].


Drs. Ridker and Cook have been critical of the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) risk assessment guideline Pooled Cohort Equations.1 In one non-peer-reviewed commentary in Lancet in 2013, they noted the Pooled Cohort Equations over-predicted atherosclerotic cardiovascular disease (ASCVD) risk in three clinical trial cohorts: the Physician's Health Study, the Women's Health Study (WHS), and the Women's Health Initiative.2 The developers of the Pooled Cohort Equations have suggested several reasons for the discrepancy, including extensive utilization of statins in higher-risk individuals contributing to the decline in ASCVD rates in contemporary U.S. populations, under-ascertainment of ASCVD events, and self-reported risk factor levels in Ridker and Cook's cohorts.3

In this peer-reviewed paper, Drs. Ridker and Cook have carefully examined whether increasing statin use over time, underascertainment of events, and revascularizations explain the discrepancy between the WHS event rates and those predicted by the Pooled Cohort Equations.4


The WHS is a nationwide cohort of U.S. women between the ages of 45-79 years and free of CVD, cancer, or other major illness at baseline between 1992-1995 (n = 27,542). All women were enrolled in a randomized trial of aspirin and vitamin E and followed for approximately 10 years. Blood pressure and medications were self-reported, although plasma lipids were measured. Annual questionnaires assessed occurrence of nonfatal CVD events, which were adjudicated based on medical records.


After adjustment for statin and revascularization effects, as well as hypothetical confounding by indication, predicted versus observed rates were 1.8 in those with 0 to <5%, 5 to <7.5% groups, and 1.30 in the 7.5 to <10% and ≥10% 10-year ASCVD risk groups.


Statin use, revascularization procedures, and underascertainment of events do not explain the discrepancy between observed and expected rates of ASCVD in WHS and those predicted by the Pooled Cohort Equations.


Cook and Ridker sidestep a key issue and, therefore, miss an important opportunity for a more nuanced interpretation of their findings. The WHS is a cohort of predominantly white, well-educated health professionals who volunteered for a clinical trial of aspirin and vitamin E. On the basis of high socioeconomic status (SES) and the healthy volunteer effect, a priori one would expect the ASCVD rates to be about 30-50% lower in WHS than a representative U.S. population.5-7 This is exactly the over-estimation that Cook & Ridker found in those with ≥7.5% risk who would be the most likely candidates for statin therapy for primary prevention of ASCVD.

The 2013 ACC/AHA blood cholesterol guideline recommends a clinician-patient discussion before initiating statin therapy for primary prevention. This discussion provides an opportunity to consider additional factors contributing to risk refinement. Notably, a person with high education/SES likely has a lower estimated 10-year and lifetime ASCVD risk than that estimated by the Pooled Cohort Equations, which were derived from and validated in contemporary representative U.S. cohorts of white and African American persons.1,8

The European CV prevention guidelines have different equations for high- and low-risk countries.9 Perhaps a future update to the U.S. ACC/AHA guidelines could consider such an approach (high- and low-risk regions? on basis of education level?) to provide guidance for refining risk estimation in white and African American women and men.


  1. Goff Jr DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59.
  2. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013;382:1762-5.
  3. Lloyd-Jones D, Goff D, Stone N. Letter to the editor: statins, risk assessment, and the new American prevention guidelines. Lancet 2014;383:600-2.
  4. Cook NR, Ridker PM. Response to comment on the reports of over-estimation of ASCVD risk using the 2013 AHA/ACC risk equation. Circulation 2014;129:268-9.
  5. Braveman PA, Cubbin C, Egerter S, Williams DR, Pamuk E. Socioeconomic disparities in health in the United States: what the patterns tell us. Am J Public Health 2010;100:S186-96.
  6. Ridker P, Danielson E, Fonseca F, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.
  7. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
  8. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease pooled cohort risk equations. JAMA 2014;311:1406-15.
  9. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Atherosclerosis 2012;223:1-68.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: African Americans, Aspirin, Atherosclerosis, Blood Pressure, Cholesterol, European Continental Ancestry Group, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Neoplasms, Medical Records, Risk, Risk Factors, Risk Assessment, Social Class, Women's Health

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