NEWS & VIEWS RISK FACTORS
New risk-assessment guidelines —more or less personalized? Michael J. Blaha and Roger S. Blumenthal
The new ACC/AHA cardiovascular-risk guidelines feature updated equations for women, distinct equations for African–American individuals, and include stroke prediction. However, the equations rely on the same traditional risk factors as previous versions, are driven predominantly by age, and curtail the intermediate-risk group, in which personalized risk assessment is recommended. Blaha, M. J. & Blumenthal, R. S. Nat. Rev. Cardiol. 11, 136–137 (2014); published online 14 January 2014; doi:10.1038/nrcardio.2013.216
Personalization is one of the ultimate goals of modern medicine. Ideally, we should be able to accurately assess the absolute cardio vascular risk of an individual patient, cal culate the likelihood of benefit or harm from an intervention, and prescribe thera pies only after a frank discussion of specific risks and benefits with a patient. For years, guidelines for the prevention of cardiovascular disease have embraced such a risk-based paradigm, linking the intensity of preventive therapy with a calculation of an individual’s absolute risk. 1 The stand ard for cardiovascular-risk assessment has been the Framingham Risk Score (FRS).1,2 However, weaknesses have emerged over time with the FRS, including concerns about whether it can be generalized to nonwhite populations, and its applicability to women. The new 2013 ACC/AHA Report on the Assessment of Cardiovascular Risk3 makes substantial progress in particular aspects of personalization. First, the new guidelines provide separate equations for men and women. Substantially improved discrimination of risk now exists among women, which has long been a problem with previous models. Second, distinct equations have been provided for white and African–American individuals, recog nizing that the determinants of disease can differ according to ethnicity. To accomplish this aim, the new ACC/AHA risk score laudably expands beyond the original Framingham cohort to include data from three other, more-diverse cohort studies funded by the US National Heart, Lung, and Blood Institute.
Importantly, the new ACC/AHA risk scores also broaden the clinical end points of interest. The FRS was designed exclu sively to predict the 10‑year risk of myo cardial infarction or death from coronary heart disease.1,2 Notably absent from this calculation was stroke, which is increas ingly recognized as an important prevent able outcome associated with enormous disability and cost, especially in women and ethnic minorities. The new ACC/ AHA risk score enables the calculation of an estimated 10‑year risk of the aggregate of coronary heart disease and stroke. In other ways, however, the new guide line falls short of increasing personaliza tion. For example, the new risk equations continue to use the same one-time meas urements of ‘traditional’ risk factors espoused in the older Framingham models: age, sex, untreated or treated systolic blood pressure, total-cholesterol and HDLcholesterol levels, current smoking status (with no adjustment for total number of pack-years or current smoking ‘dose’), and presence of diabetes mellitus (but no con sideration of duration since diagnosis or severity of hyperglycaemia). For example, a family history of premature coronary heart disease, although asked by nearly every clinician around the world, continues to be absent from the models.4 Also absent are any measures of diet, exercise, or impaired fasting glucose. Despite >2 decades of research on novel biomarkers of risk, the new risk score is structurally the same as the original FRS. 5 Not surprisingly, the overall accuracy of risk estimates produced
NATURE REVIEWS | CARDIOLOGY
using the new risk score is very similar to that using past models. Age continues to be the dominant factor in the new risk equations. Age has con founded nearly every attempt to predict the onset of preventable chronic disease in modern medicine. Although certainly a powerful marker of risk, age—being a nonmodifiable factor that inexorably increases with time—by definition limits the personalization of treatment. From one perspective, the new ACC/AHA risk score is a complicated mathematical expression of the adage ‘older people have more heart attacks and strokes’. With the new risk score, nearly every man aged >60 years will be considered to be at high cardio vascular risk (and, therefore, deserving of statin medication).
‘‘
…the new 2013 ACC/AHA risk score is a small step towards personalization of medical care…
’’
The issue of age becomes even more complicated in the light of preliminary, but consistent, data showing that the new risk score systematically overestimates absolute risk in ‘modern’ populations (that is, in individuals with contemporary riskfactor exposure and medical therapies). In the ‘contemporary years’ of the derivation cohorts, 3 as well as in the more-modern MESA, REGARDS, and Women’s Health Initiative studies,6 the new risk score places a substantial number of patients in highrisk groups when, in fact, the observed event rates are not commensurately high. An urgent need exists for further research into the causes and implications of over estimation. In our view, many patients considered to be at high risk on the basis of chronological age alone (many even in the absence of risk factors) might not be truly high risk. Using previous guidelines, a large intermediate-risk group (6–20% or 10–20% 10‑year risk of developing coronary heart disease) was identified, and treatment deci sions were not well defined in these patients. The intermediate-risk group has been fertile ground for hundreds of advanced VOLUME 11 | MARCH 2014
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Old risk score High risk
New risk score
Intermediate risk
Low risk
Figure 1 | The Framingham Risk Score, and adapted versions in previous guidelines, was used to identify a large group of intermediaterisk patients for whom further testing to enhance risk stratification was recommended. The new 2013 ACC/AHA risk score substantially narrows the intermediate-risk group, predominantly moving patients into the high-risk group. This change reduces the opportunity for physicians to consider further testing to personalize risk estimates.
risk-prediction papers.7 In these patients, a variety of other tests have emerged as legitimate options for enhanced risk strat ification, including serum biomarkers, such as C‑reactive protein measured by highsensitivity assay, and imaging tests, such as coronary artery calcium (CAC) scanning.8 In the 2013 ACC/AHA guidelines, new ‘clinically meaningful cut points’ have been defined for the identification of low-risk, intermediate-risk, and high-risk patients (0.0–4.9%, 5.0–7.4%, and ≥7.5% 10‑year risk, respectively). 3 In the past, experts pushed for an expanded intermediate-risk group,9 whereas in the new risk algorithm, the intermediate-risk group is narrower than ever. Using the previous Framinghambased Adult Treatment Panel III calcu lator, approximately 33% of adult patients aged 40–79 years were considered to be at intermediate risk. With the new risk score, this number has dropped to about 13%, including only 10% of women (Figure 1). Given the importance assigned to age in the risk score, coupled with the narrow intermediate-risk group, nearly all cur rently intermediate-risk patients will pro gress to high risk in a few years on the basis of advancing age alone. Why even consider
MARCH 2014 | VOLUME 11
further prognostic tests? In this way, the new guidelines reduce the opportunities for personalizing risk assessment. This trend is unfortunate, because imaging tests, such as the CAC score, which gives a direct estimate of the burden of coronary athero sclerosis in an individual patient, provide far more personalized risk assessment than one-time measurements of risk factors, and suffer less from the problems inherent in generalizing from populations to individual patients.8,10 Perhaps, in the near future, the intermediate-risk range could be expanded to include those with a 10‑year risk of 5.0–10.0% or 5.0–15.0%. The 2013 ACC/AHA risk-assessment tool is a great achievement and is the result of much of the progress we have made in cardiovascular epidemiology. The authors should be commended for improving risk assessment in women. Unfortunately, whether the equations have improved risk prediction in contemporary African– American individuals remains question able, because validation data from the MESA and REGARDS cohorts showed very poor performance in this ethnic group. 3 Men aged 62 years without risk factors who want to avoid taking medications might have preferred the FRS and the previous treatment guidelines. In the next decade, the time will come to move away from generalized risk estimates calculated by inference from large popu lations, and towards increasingly person alized risk assessment via measurement of subclinical atherosclerosis, and perhaps sub sequently with insights from genetic testing. For now, the new 2013 ACC/AHA risk score is a small step towards personalization of medical care in terms of sex and ethnicity, and we hope that the tool is quickly adopted into electronic medical records around the world. In the next few years, we expect revi sions to the risk score, incorporating diverse data from modern populations, and emerg ing data from novel risk markers, such as measurements of CAC.
The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Carnegie 565A, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287, USA (M. J. Blaha, R. S. Blumenthal). Correspondence to: M. J. Blaha [email protected] Competing interests The authors declare no competing interests. 1.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285, 2486–2497 (2001). 2. Wilson, P. W. et al. Prediction of coronary heart disease using risk factor categories. Circulation 97, 1837–1847 (1998). 3. Goff, D. C. Jr 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. http:// dx.doi.org/10.1016/j.jacc.2013.11.005. 4. Pandey, A. K. et al. Family history of coronary heart disease and the incidence and progression of coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 115, 2722–2730 (2013). 5. Ioannidis, J. P. More than a billion people taking statins? Potential implications of the new cardiovascular guidelines. JAMA http:// dx.doi.org/10.1001/jama.2013.284657. 6. Ridker, P. M. & Cook, N. R. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 382, 1762–1765 (2013). 7. Yeboah, J. et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 308, 788–795 (2012). 8. Blaha, M. J. et al. Associations between C‑reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a populationbased cohort study. Lancet 378, 684–692 (2011). 9. Taylor, A. J., Merz, C. N. & Udelson, J. E. 34th Bethesda Conference: executive summary—can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease? J. Am. Coll. Cardiol. 41, 1860–1862 (2003). 10. Silverman, M. G. et al. Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis (MESA). Eur. Heart J. (in press).
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
New risk-assessment guidelines —more or less personalized? Michael J. Blaha and Roger S. Blumenthal
The new ACC/AHA cardiovascular-risk guidelines feature updated equations for women, distinct equations for African–American individuals, and include stroke prediction. However, the equations rely on the same traditional risk factors as previous versions, are driven predominantly by age, and curtail the intermediate-risk group, in which personalized risk assessment is recommended. Blaha, M. J. & Blumenthal, R. S. Nat. Rev. Cardiol. 11, 136–137 (2014); published online 14 January 2014; doi:10.1038/nrcardio.2013.216
Personalization is one of the ultimate goals of modern medicine. Ideally, we should be able to accurately assess the absolute cardio vascular risk of an individual patient, cal culate the likelihood of benefit or harm from an intervention, and prescribe thera pies only after a frank discussion of specific risks and benefits with a patient. For years, guidelines for the prevention of cardiovascular disease have embraced such a risk-based paradigm, linking the intensity of preventive therapy with a calculation of an individual’s absolute risk. 1 The stand ard for cardiovascular-risk assessment has been the Framingham Risk Score (FRS).1,2 However, weaknesses have emerged over time with the FRS, including concerns about whether it can be generalized to nonwhite populations, and its applicability to women. The new 2013 ACC/AHA Report on the Assessment of Cardiovascular Risk3 makes substantial progress in particular aspects of personalization. First, the new guidelines provide separate equations for men and women. Substantially improved discrimination of risk now exists among women, which has long been a problem with previous models. Second, distinct equations have been provided for white and African–American individuals, recog nizing that the determinants of disease can differ according to ethnicity. To accomplish this aim, the new ACC/AHA risk score laudably expands beyond the original Framingham cohort to include data from three other, more-diverse cohort studies funded by the US National Heart, Lung, and Blood Institute.
Importantly, the new ACC/AHA risk scores also broaden the clinical end points of interest. The FRS was designed exclu sively to predict the 10‑year risk of myo cardial infarction or death from coronary heart disease.1,2 Notably absent from this calculation was stroke, which is increas ingly recognized as an important prevent able outcome associated with enormous disability and cost, especially in women and ethnic minorities. The new ACC/ AHA risk score enables the calculation of an estimated 10‑year risk of the aggregate of coronary heart disease and stroke. In other ways, however, the new guide line falls short of increasing personaliza tion. For example, the new risk equations continue to use the same one-time meas urements of ‘traditional’ risk factors espoused in the older Framingham models: age, sex, untreated or treated systolic blood pressure, total-cholesterol and HDLcholesterol levels, current smoking status (with no adjustment for total number of pack-years or current smoking ‘dose’), and presence of diabetes mellitus (but no con sideration of duration since diagnosis or severity of hyperglycaemia). For example, a family history of premature coronary heart disease, although asked by nearly every clinician around the world, continues to be absent from the models.4 Also absent are any measures of diet, exercise, or impaired fasting glucose. Despite >2 decades of research on novel biomarkers of risk, the new risk score is structurally the same as the original FRS. 5 Not surprisingly, the overall accuracy of risk estimates produced
NATURE REVIEWS | CARDIOLOGY
using the new risk score is very similar to that using past models. Age continues to be the dominant factor in the new risk equations. Age has con founded nearly every attempt to predict the onset of preventable chronic disease in modern medicine. Although certainly a powerful marker of risk, age—being a nonmodifiable factor that inexorably increases with time—by definition limits the personalization of treatment. From one perspective, the new ACC/AHA risk score is a complicated mathematical expression of the adage ‘older people have more heart attacks and strokes’. With the new risk score, nearly every man aged >60 years will be considered to be at high cardio vascular risk (and, therefore, deserving of statin medication).
‘‘
…the new 2013 ACC/AHA risk score is a small step towards personalization of medical care…
’’
The issue of age becomes even more complicated in the light of preliminary, but consistent, data showing that the new risk score systematically overestimates absolute risk in ‘modern’ populations (that is, in individuals with contemporary riskfactor exposure and medical therapies). In the ‘contemporary years’ of the derivation cohorts, 3 as well as in the more-modern MESA, REGARDS, and Women’s Health Initiative studies,6 the new risk score places a substantial number of patients in highrisk groups when, in fact, the observed event rates are not commensurately high. An urgent need exists for further research into the causes and implications of over estimation. In our view, many patients considered to be at high risk on the basis of chronological age alone (many even in the absence of risk factors) might not be truly high risk. Using previous guidelines, a large intermediate-risk group (6–20% or 10–20% 10‑year risk of developing coronary heart disease) was identified, and treatment deci sions were not well defined in these patients. The intermediate-risk group has been fertile ground for hundreds of advanced VOLUME 11 | MARCH 2014
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Old risk score High risk
New risk score
Intermediate risk
Low risk
Figure 1 | The Framingham Risk Score, and adapted versions in previous guidelines, was used to identify a large group of intermediaterisk patients for whom further testing to enhance risk stratification was recommended. The new 2013 ACC/AHA risk score substantially narrows the intermediate-risk group, predominantly moving patients into the high-risk group. This change reduces the opportunity for physicians to consider further testing to personalize risk estimates.
risk-prediction papers.7 In these patients, a variety of other tests have emerged as legitimate options for enhanced risk strat ification, including serum biomarkers, such as C‑reactive protein measured by highsensitivity assay, and imaging tests, such as coronary artery calcium (CAC) scanning.8 In the 2013 ACC/AHA guidelines, new ‘clinically meaningful cut points’ have been defined for the identification of low-risk, intermediate-risk, and high-risk patients (0.0–4.9%, 5.0–7.4%, and ≥7.5% 10‑year risk, respectively). 3 In the past, experts pushed for an expanded intermediate-risk group,9 whereas in the new risk algorithm, the intermediate-risk group is narrower than ever. Using the previous Framinghambased Adult Treatment Panel III calcu lator, approximately 33% of adult patients aged 40–79 years were considered to be at intermediate risk. With the new risk score, this number has dropped to about 13%, including only 10% of women (Figure 1). Given the importance assigned to age in the risk score, coupled with the narrow intermediate-risk group, nearly all cur rently intermediate-risk patients will pro gress to high risk in a few years on the basis of advancing age alone. Why even consider
MARCH 2014 | VOLUME 11
further prognostic tests? In this way, the new guidelines reduce the opportunities for personalizing risk assessment. This trend is unfortunate, because imaging tests, such as the CAC score, which gives a direct estimate of the burden of coronary athero sclerosis in an individual patient, provide far more personalized risk assessment than one-time measurements of risk factors, and suffer less from the problems inherent in generalizing from populations to individual patients.8,10 Perhaps, in the near future, the intermediate-risk range could be expanded to include those with a 10‑year risk of 5.0–10.0% or 5.0–15.0%. The 2013 ACC/AHA risk-assessment tool is a great achievement and is the result of much of the progress we have made in cardiovascular epidemiology. The authors should be commended for improving risk assessment in women. Unfortunately, whether the equations have improved risk prediction in contemporary African– American individuals remains question able, because validation data from the MESA and REGARDS cohorts showed very poor performance in this ethnic group. 3 Men aged 62 years without risk factors who want to avoid taking medications might have preferred the FRS and the previous treatment guidelines. In the next decade, the time will come to move away from generalized risk estimates calculated by inference from large popu lations, and towards increasingly person alized risk assessment via measurement of subclinical atherosclerosis, and perhaps sub sequently with insights from genetic testing. For now, the new 2013 ACC/AHA risk score is a small step towards personalization of medical care in terms of sex and ethnicity, and we hope that the tool is quickly adopted into electronic medical records around the world. In the next few years, we expect revi sions to the risk score, incorporating diverse data from modern populations, and emerg ing data from novel risk markers, such as measurements of CAC.
The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Carnegie 565A, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287, USA (M. J. Blaha, R. S. Blumenthal). Correspondence to: M. J. Blaha [email protected] Competing interests The authors declare no competing interests. 1.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285, 2486–2497 (2001). 2. Wilson, P. W. et al. Prediction of coronary heart disease using risk factor categories. Circulation 97, 1837–1847 (1998). 3. Goff, D. C. Jr 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. http:// dx.doi.org/10.1016/j.jacc.2013.11.005. 4. Pandey, A. K. et al. Family history of coronary heart disease and the incidence and progression of coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 115, 2722–2730 (2013). 5. Ioannidis, J. P. More than a billion people taking statins? Potential implications of the new cardiovascular guidelines. JAMA http:// dx.doi.org/10.1001/jama.2013.284657. 6. Ridker, P. M. & Cook, N. R. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 382, 1762–1765 (2013). 7. Yeboah, J. et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 308, 788–795 (2012). 8. Blaha, M. J. et al. Associations between C‑reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a populationbased cohort study. Lancet 378, 684–692 (2011). 9. Taylor, A. J., Merz, C. N. & Udelson, J. E. 34th Bethesda Conference: executive summary—can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease? J. Am. Coll. Cardiol. 41, 1860–1862 (2003). 10. Silverman, M. G. et al. Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis (MESA). Eur. Heart J. (in press).
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
