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).
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.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127-e248.
- Goff DC Jr, 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.
- Nanna MG, Peterson ED, Wojdyla D, Navar AM. The accuracy of cardiovascular pooled cohort risk estimates in U.S. older adults. J Gen Intern Med 2019. [epub ahead of print].
- Roberts AW, Ogunwole SU, Blakeslee L., Rabe MA. The Population 65 years and Older in the United States: 2016 (United States Census Bureau website). 2018. Available at: https://www.census.gov/content/dam/Census/library/publications/2018/acs/ACS-38.pdf. Accessed 04/01/2020.
- Heron M. Deaths: Leading Causes for 2016. (US Department of Health and Human Services website). 2018. Available at: https://www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_06.pdf. Accessed 04/01/2020.
- Virani SS, Alonso A, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2020 Update: a report from the American Heart Association. Circulation 2020;141:e139-e596.
- Disdier Moulder MPA, Hendricks AK, Ou NN. Towards appropriate polypharmacy in older cardiovascular patients: how many medications do I have to take? Clinl Cardiol 2020;43:137-44.
- Schwartz JB, Schmader KE, Hanlon JT, et al. Pharmacotherapy in older adults with cardiovascular disease: report from an American College of Cardiology, American Geriatrics Society, and National Institute on Aging Workshop. J Am Geriatr Soc 2019;67:371-80.
- Shah RC, Supiano MA, Greenland P. Aligning the 4Ms of age-friendly health systems with statin use for primary prevention. J Am Geriatr Soc 2020;68:463-64.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:3168-3209.
- Nanna MG, Navar AM, Wojdyla D, Peterson ED. The association between low-density lipoprotein cholesterol and incident atherosclerotic cardiovascular disease in older adults: results from the National Institutes of Health Pooled Cohorts. J Am Geriatr Soc 2019;67:2560-67.
- Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
- Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014;64:485-94.
- Puri R, Nissen SE, Shao M, et al. Impact of baseline lipoprotein and c-reactive protein levels on coronary atheroma regression following high-intensity statin therapy. Am J Cardiol 2014;114:1465-72.
- Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;390:1962-71.
- Navarese EP, Robinson JG, Kowalewski M, et al. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA 2018;319:1566-79.
- Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 2019;393:407-15.
- A clinical trial of Statin therapy for reducing events in the elderly (STAREE) (ClinicalTrials.gov. website). 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT02099123 Accessed 04/01/2020.
- Forman DE, Maurer MS, Boyd C, et al. Multimorbidity in older adults with cardiovascular disease. J Am Coll Cardiol 2018;71:2149-61.
- Afilalo J. Frailty in patients with cardiovascular disease: why, when, and how to measure. Curr Cardiovasc Risk Rep 2011;5:467-72.
- Newman AB, Simonsick EM, Naydeck BL, et al. Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 2006;295:2018-26.
- Plichart M, Barberger-Gateau P, Tzourio C, et al. Disability and incident coronary heart disease in older community-dwelling adults: the three-city study. J Am Geriatr Soc 2010;58:636-42.
- An J, Li H, Tang Z, et al. Cognitive impairment and risk of all-cause and cardiovascular disease mortality over 20-year follow-up: results from the BLSA. JAHA 2018;7:e008252.
- Boyd C, Smith CD, Masoudi FA, et al. Decision making for older adults with multiple chronic conditions: executive summary for the American Geriatrics Society Guiding Principles on the Care of Older Adults with Multimorbidity. J Am Geriatr Soc 2019;67:665-73.
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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