Failure of Traditional Risk Factors to Adequately Predict Cardiovascular Events in Older Populations

Editor's Note: Commentary based on Dalton JE, Rothberg MD, Dawson NV, Krieger NI, Zidar DA, Perzynski AD. Failure of Traditional Risk Factors to Adequately Predict Cardiovascular Events in Older Populations. J Am Geriatr Soc. 2020. [epub ahead of print].

Rationale for Study/Background:
Accurate characterization of future atherosclerotic cardiovascular disease (ASCVD) risk is a central component guiding patient-centered care for primary prevention of CVD. The American College of Cardiology and American Heart Association (ACC/AHA) recommend using the Pooled Cohort Equations (PCE) risk model1,2 to guide risk discussions, but this model was neither developed nor validated for individuals ≥80 years old. Recent studies have identified suboptimal performance of the PCE in adults ≥75 years of age.3 Furthermore, the PCE assume a fixed relationship between clinical risk factors and ASCVD risk as patients age, which ignores the likelihood that these associations may change with physiologic aging. Thus, in this study, the investigators set out to 1) evaluate the performance of the PCE in adults ≥65 years; 2) assess the predictive value of individual traditional risk factors in older populations; and 3) determine whether risk prediction can be improved by updating model coefficients for traditional clinical risk factors based on age.

Funding: Supported by The National Institute on Aging of the National Institutes of Health under award R01AG055480.

Methods: This study used retrospective electronic health record data from 26,772 patients ≥65 years old seen in the Cleveland Clinic Health System who were free of ASCVD and had an out-patient lipid panel between 2007 and 2010. Vital status was supplemented using data from the Ohio Department of Health.

Design: Retrospective cohort

Inclusion Criteria: Adults ≥65 years with an outpatient lipid panel between 2007 and 2010 and without known ASCVD.

Exclusion Criteria: Individuals not of white or African American race. Individuals with incomplete data needed to calculate the PCE.

Measurements: Time to major ASCVD event (stroke, myocardial infarction, or cardiovascular death).

Statistical Analysis:
The authors evaluated performance of the PCE within three age groups: 65-74, 75-84, and ≥85 years. Model discrimination was assessed by the concordance index and calibration with calibration plots. Updated associations between cardiovascular risk factors included in the PCE and time to first ASCVD event were estimated using stratified Cox regression models for each of the three age groups. Subjects on statins were included with a 21% adjustment for total cholesterol and 3.5% adjustment for HDL cholesterol, as well as a 21% reduction in 5-year ASCVD risk. Sensitivity analyses excluding patients on statins were also conducted.

Results: A total of 26,349 patients were included in the analysis, comprising 15,290 age 65-74, 8082 age 75-84, and 1977 ≥85 years old. Discrimination of the PCE was poor across all three age groups (C-index 0.62 in 65-74, 0.56 in 75-84, and 0.52 in the ≥85 age group); calibration was moderate in the 65-74 group but suboptimal in the older age groups. Internally estimated stratified Cox regression models revealed that age, low HDL (≤40 mg/dL), antihypertensive drug use and smoking were associated with time to first ASCVD event across all age groups. African American race and systolic blood pressure >140 mmHg was only significantly associated with events in the 65-74-year age group and diabetes was associated with events in those 65-74 and 75-84 years but not in the oldest age group. Conversely, total cholesterol in the 151-200 and 201-250 mg/dL ranges were associated with decreased risk (compared to cholesterol <150 mg/dL) across all age groups. The PCE and the internal risk models yielded similar results for white men 65-74 years old, but the PCE produced lower risk predictions in all other groups. The updated internal risk model improved both discrimination and calibration beyond the PCE, though discrimination was still limited (C-index 0.67 in 65-74, 0.61 ≥75). Sensitivity analyses excluding patients on statins yielded similar calibration and discrimination.

Limitations of study: The study consisted of a largely middle- to upper-class population from a single health system, which may limit the generalizability of the results to the broader US population. Geriatric specific factors such as frailty and functional status were not assessed in this study and may contribute to future cardiovascular risk; the predictive value of these factors is worthy of future evaluation. While total cholesterol levels in this study >150 mg/dL up to 250 mg/dL appeared to be inversely related to adverse events (reverse epidemiology), this does not inform us about the efficacy of lipid-lowering therapy in this population (see below). Thus, the authors' assertion that these findings "cast doubt" on the efficacy of lipid-lowering therapies is potentially unfounded.

Conclusion: The traditional cardiovascular risk factors included in the PCE do not accurately discriminate risk in older adults, even when relationships between those risk factors and ASCVD events are re-estimated within age groups. New geriatric-specific risk models are necessary to guide treatment decisions in this complex population.

Geriatric perspective for the cardiovascular clinician:
As the United States population ages,4 cardiovascular primary prevention decisions in older adults will become an increasingly common clinical challenge. These decisions carry high stakes: cardiovascular disease remains the number one cause of morbidity and mortality in older Americans.5,6 However, treatment decisions regarding primary prevention are complex in older adults and all medications have potential risk.7-9 A baseline ASCVD risk assessment is the first step to guide shared-decision-making discussions around statin use in eligible patients,10 and the ACC/AHA guideline recommends the PCE for risk estimation. Unfortunately, prior studies have suggested poor performance of the PCE in older adults,3 a finding confirmed by the current study. In fact, among individuals ≥75 years old, the PCE performance was barely better than a coin flip in the >10,000 patients assessed. This appears to be largely driven by the lack of predictive value of traditional cardiovascular risk factors as patients age. While certain risk factors remained predictive (low HDL, antihypertensive use, and smoking), the associations of African American race, systolic blood pressure >140 mmHg, diabetes and total cholesterol with ASCVD risk all significantly changed with increasing age.

In particular, the authors' findings that total cholesterol was inversely related to ASCVD risk merits closer evaluation. This relationship is in line with recent data from the pooled cohorts demonstrating a lack of association between LDL-cholesterol and cardiovascular risk in a population ≥75 years old.11 However, while these findings reflect the association between cholesterol as a risk factor and future cardiovascular risk, they should not be misinterpreted as suggesting lack of benefit for lipid-lowering therapies in older adults. In fact, prior studies have demonstrated the benefit of cholesterol lowering across a variety of starting cholesterol levels and with no lower LDL-C limit for risk reduction,12-16 albeit with limited numbers of older adults. Some have suggested an attenuated effect of statin therapy in primary prevention from prior randomized trials in older adults,17 but dedicated randomized controlled trials will be necessary to definitively address the role of statins in older individuals (and are currently in the pipeline!).18

Ultimately, while younger patients' cardiovascular risk may be derived from a constellation of traditional risk factors, assessment of ASCVD risk in older adults is far more complex. Many factors operate on both sides of the risk equation in older adults, presenting both as risk factors for developing ASCVD while also posing a competing risk for non-cardiovascular death. Examples include multimorbidity,19 frailty,20,21 functional limitations,22 cognitive impairment,23 and polypharmacy,8 all of which often factor into prevention treatment decisions in this population. Future ASCVD risk models incorporating more geriatric-specific risk factors will be necessary to inform primary prevention decisions in older adults, but no risk prediction model will be sufficient to fully inform effective shared decision-making. Health trajectory must be factored into the broader context of patient priorities and individual goals of care in order to optimize preventive care in older adults.24

Take home message: The PCE provide limited utility to guide primary prevention risk discussions in older adults. This is due to the limited predictive value of traditional cardiovascular risk factors in this population. New cardiovascular risk models incorporating novel risk markers are needed.


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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Geriatric Cardiology, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Geriatrics, Cholesterol, LDL, Cholesterol, HDL, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, American Heart Association, Antihypertensive Agents, Cardiovascular Diseases, Outpatients, Blood Pressure, Retrospective Studies, National Institute on Aging (U.S.), Electronic Health Records, Frail Elderly

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