Skip to main content

Advertisement

Log in

The Use of Risk-Enhancing Factors to Personalize ASCVD Risk Assessment: Evidence and Recommendations from the 2018 AHA/ACC Multi-Society Cholesterol Guidelines

  • Lipids (E Michos, Section Editor)
  • Published:
Current Cardiovascular Risk Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

In 2018, the AHA/ACC Multi-Society Cholesterol Guidelines introduced the novel concept of risk-enhancing factors to be used as a supplement to the pooled cohort risk equations to personalize atherosclerotic cardiovascular disease risk assessment in primary prevention. In this review, we discuss the rationale and evidence behind each of the risk-enhancing factors to help clinicians perform a more personalized cardiovascular risk assessment.

Recent Findings

The risk-enhancing factors are high-risk features that may guide the use of lipid-lowering therapy particularly in intermediate and select borderline-risk patients. For the purpose of this review, these factors are divided into five categories: (i) race and genetics, (ii) conditions specific to women, (iii) lipid-related risk, (iv) concurrent high-risk medical conditions, and (v) biomarkers.

Summary

The addition of the risk-enhancing factors to the pooled cohort equations provides a more individualized and comprehensive approach to cardiovascular disease risk assessment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol. Circulation. 2018;2018:CIR0000000000000625.

    Google Scholar 

  2. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, 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(25 Pt B):2889–934.

    Article  PubMed  Google Scholar 

  3. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019.

  4. Kavousi M, Leening MJ, Nanchen D, Greenland P, Graham IM, Steyerberg EW, et al. Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort. JAMA. 2014;311(14):1416–23.

    Article  PubMed  Google Scholar 

  5. Wolfson J, Vock DM, Bandyopadhyay S, Kottke T, Vazquez-Benitez G, Johnson P, et al. Use and customization of risk scores for predicting cardiovascular events using electronic health record data. J Am Heart Assoc. 2017;6(4).

  6. Goff DC, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R, 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. Circulation. 2014;129(25 Suppl 2):S49–73.

    Article  PubMed  Google Scholar 

  7. Muntner P, Colantonio LD, Cushman M, Goff DC, Howard G, Howard VJ, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA. 2014;311(14):1406–15.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lloyd-Jones DM, Nam BH, D'Agostino RB, Levy D, Murabito JM, Wang TJ, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA. 2004;291(18):2204–11.

    Article  CAS  PubMed  Google Scholar 

  9. Weijmans M, van der Graaf Y, Reitsma JB, Visseren FL. Paternal or maternal history of cardiovascular disease and the risk of cardiovascular disease in offspring. A systematic review and meta-analysis. Int J Cardiol. 2015;179:409–16.

    Article  CAS  PubMed  Google Scholar 

  10. •• Volgman AS, Palaniappan LS, Aggarwal NT, Gupta M, Khandelwal A, Krishnan AV, et al. Atherosclerotic cardiovascular disease in south Asians in the United States: epidemiology, risk factors, and treatments: a scientific statement from the American Heart Association. Circulation. 2018;138(1):e1–e34. This paper summarizes the evidence and risk factors behind the increased risk of ASCVD in South Asians.

    Article  PubMed  Google Scholar 

  11. Jose PO, Frank AT, Kapphahn KI, Goldstein BA, Eggleston K, Hastings KG, et al. Cardiovascular disease mortality in Asian Americans. J Am Coll Cardiol. 2014;64(23):2486–94.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Karthikeyan G, Teo KK, Islam S, McQueen MJ, Pais P, Wang X, et al. Lipid profile, plasma apolipoproteins, and risk of a first myocardial infarction among Asians: an analysis from the INTERHEART Study. J Am Coll Cardiol. 2009;53(3):244–53.

    Article  CAS  PubMed  Google Scholar 

  13. Joshi P, Islam S, Pais P, Reddy S, Dorairaj P, Kazmi K, et al. Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA. 2007;297(3):286–94.

    Article  CAS  PubMed  Google Scholar 

  14. •• Paré G, Çaku A, McQueen M, Anand SS, Enas E, Clarke R, et al. Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups. Circulation. 2019;139(12):1472–82. This study highlights ethnic differences in Lp(a) isoform size distribution and concentrations among multiple ethnic groups.

    Article  PubMed  Google Scholar 

  15. Muka T, Oliver-Williams C, Kunutsor S, Laven JS, Fauser BC, Chowdhury R, et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol. 2016;1(7):767–76.

    Article  PubMed  Google Scholar 

  16. Ley SH, Li Y, Tobias DK, Manson JE, Rosner B, Hu FB, et al. Duration of reproductive life span, age at menarche, and age at menopause are associated with risk of cardiovascular disease in women. J Am Heart Assoc. 2017;6(11).

  17. Roeters van Lennep JE, Heida KY, Bots ML, Hoek A, Disorders cotDMGDGoCRMaR. Cardiovascular disease risk in women with premature ovarian insufficiency: a systematic review and meta-analysis. Eur J Prev Cardiol. 2016;23(2):178–86.

    Article  PubMed  Google Scholar 

  18. Ahmed R, Dunford J, Mehran R, Robson S, Kunadian V. Pre-eclampsia and future cardiovascular risk among women: a review. J Am Coll Cardiol. 2014;63(18):1815–22.

    Article  PubMed  Google Scholar 

  19. Brown MC, Best KE, Pearce MS, Waugh J, Robson SC, Bell R. Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis. Eur J Epidemiol. 2013;28(1):1–19.

    Article  PubMed  Google Scholar 

  20. Grandi SM, Vallée-Pouliot K, Reynier P, Eberg M, Platt RW, Arel R, et al. Hypertensive disorders in pregnancy and the risk of subsequent cardiovascular disease. Paediatr Perinat Epidemiol. 2017;31(5):412–21.

    Article  PubMed  Google Scholar 

  21. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet. 2005;366(9499):1797–803.

    Article  PubMed  Google Scholar 

  22. Shostrom DCV, Sun Y, Oleson JJ, Snetselaar LG, Bao W. History of gestational diabetes mellitus in relation to cardiovascular disease and cardiovascular risk factors in US women. Front Endocrinol (Lausanne). 2017;8:144.

    Article  Google Scholar 

  23. Retnakaran R, Shah BR. Mild glucose intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. CMAJ. 2009;181(6–7):371–6.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Carr DB, Utzschneider KM, Hull RL, Tong J, Wallace TM, Kodama K, et al. Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history of type 2 diabetes. Diabetes Care. 2006;29(9):2078–83.

    Article  PubMed  Google Scholar 

  25. Catov JM, Newman AB, Roberts JM, Kelsey SF, Sutton-Tyrrell K, Harris TB, et al. Preterm delivery and later maternal cardiovascular disease risk. Epidemiology. 2007;18(6):733–9.

    Article  PubMed  Google Scholar 

  26. Sattar N. Do pregnancy complications and CVD share common antecedents? Atheroscler Suppl. 2004;5(2):3–7.

    Article  PubMed  Google Scholar 

  27. DeFranco E, Teramo K, Muglia L. Genetic influences on preterm birth. Semin Reprod Med. 2007;25(1):40–51.

    Article  CAS  PubMed  Google Scholar 

  28. •• Abdullah SM, Defina LF, Leonard D, Barlow CE, Radford NB, Willis BL, et al. Long-term association of low-density lipoprotein cholesterol with cardiovascular mortality in individuals at low 10-year risk of atherosclerotic cardiovascular disease. Circulation. 2018;138(21):2315–25. This study shows that even in a low risk cohort, LDL-C and non-HDL-C ≥ 160 mg/dL are independently associated with a 50% to 80% increased relative risk of CVD mortality.

    Article  CAS  PubMed  Google Scholar 

  29. Virani SS, Ballantyne CM. Low-density lipoprotein cholesterol: is 160 the new 190? Circulation. 2018;138(21):2326–9.

    Article  PubMed  Google Scholar 

  30. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993–2000.

    Article  PubMed  Google Scholar 

  31. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3(2):213–9.

    Article  CAS  PubMed  Google Scholar 

  32. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298(3):299–308.

    Article  CAS  PubMed  Google Scholar 

  33. Karlson BW, Palmer MK, Nicholls SJ, Lundman P, Barter PJ. A VOYAGER meta-analysis of the impact of statin therapy on low-density lipoprotein cholesterol and triglyceride levels in patients with hypertriglyceridemia. Am J Cardiol. 2016;117(9):1444–8.

    Article  CAS  PubMed  Google Scholar 

  34. Herrington WG, Emberson J, Mihaylova B, Blackwell L, Reith C, Solbu MD, et al. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol. 2016;4(10):829–39.

    Article  PubMed  Google Scholar 

  35. Bauer RC, Khetarpal SA, Hand NJ, Rader DJ. Therapeutic targets of triglyceride metabolism as informed by human genetics. Trends Mol Med. 2016;22(4):328–40.

    Article  CAS  PubMed  Google Scholar 

  36. Thomsen M, Varbo A, Tybjærg-Hansen A, Nordestgaard BG. Low nonfasting triglycerides and reduced all-cause mortality: a Mendelian randomization study. Clin Chem. 2014;60(5):737–46.

    Article  CAS  PubMed  Google Scholar 

  37. Lee AJ, Price JF, Russell MJ, Smith FB, van Wijk MC, Fowkes FG. Improved prediction of fatal myocardial infarction using the ankle brachial index in addition to conventional risk factors: the Edinburgh Artery Study. Circulation. 2004;110(19):3075–80.

    Article  CAS  PubMed  Google Scholar 

  38. Yeboah J, McClelland RL, Polonsky TS, Burke GL, Sibley CT, O'Leary D, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA. 2012;308(8):788–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59(12):1690–7.

    Article  PubMed  Google Scholar 

  40. Westerweel PE, Luyten RK, Koomans HA, Derksen RH, Verhaar MC. Premature atherosclerotic cardiovascular disease in systemic lupus erythematosus. Arthritis Rheum. 2007;56(5):1384–96.

    Article  PubMed  Google Scholar 

  41. Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J. 2010;31(8):1000–6.

    Article  PubMed  Google Scholar 

  42. Dregan A, Chowienczyk P, Molokhia M. Cardiovascular and type 2 diabetes morbidity and all-cause mortality among diverse chronic inflammatory disorders. Heart. 2017;103(23):1867–73.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Fernández-Montero JV, Barreiro P, de Mendoza C, Labarga P, Soriano V. Hepatitis C virus coinfection independently increases the risk of cardiovascular disease in HIV-positive patients. J Viral Hepat. 2016;23(1):47–52.

    Article  PubMed  Google Scholar 

  44. Feinstein MJ, Nance RM, Drozd DR, Ning H, Delaney JA, Heckbert SR, et al. Assessing and refining myocardial infarction risk estimation among patients with human immunodeficiency virus: a study by the centers for AIDS Research Network of Integrated Clinical Systems. JAMA Cardiol. 2017;2(2):155–62.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, et al. The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;56(14):1113–32.

    Article  PubMed  Google Scholar 

  46. Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol. 2007;49(4):403–14.

    Article  CAS  PubMed  Google Scholar 

  47. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073–81.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wilson PW, Pencina M, Jacques P, Selhub J, D'Agostino R, O'Donnell CJ. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes. 2008;1(2):92–7.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132–40.

    Article  PubMed  Google Scholar 

  51. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.

    Article  CAS  PubMed  Google Scholar 

  52. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Am J Cardiol. 2010;106(2):204–9.

    Article  CAS  PubMed  Google Scholar 

  53. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412–23.

    Article  CAS  PubMed  Google Scholar 

  54. • Verbeek R, Hoogeveen RM, Langsted A, Stiekema LCA, Verweij SL, Hovingh GK, et al. Cardiovascular disease risk associated with elevated lipoprotein(a) attenuates at low low-density lipoprotein cholesterol levels in a primary prevention setting. Eur Heart J. 2018;39(27):2589–96. This study demonstrates that both Lp(a) and LDL-C levels are independent risk factors for CVD. However, at LDL-C levels below < 2.5 mmol/L, the risk associated with elevated Lp(a) is attenuated in a primary prevention setting.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Virani SS, Brautbar A, Davis BC, Nambi V, Hoogeveen RC, Sharrett AR, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2012;125(2):241–9.

    Article  CAS  PubMed  Google Scholar 

  56. Cook NR, Mora S, Ridker PM. Lipoprotein(a) and cardiovascular risk prediction among women. J Am Coll Cardiol. 2018;72(3):287–96.

    Article  CAS  PubMed  Google Scholar 

  57. • Burgess S, Ference BA, Staley JR, Freitag DF, Mason AM, Nielsen SF, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–27. This study shows that lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Di Angelantonio E, Gao P, Pennells L, Kaptoge S, Caslake M, Thompson A, et al. Lipid-related markers and cardiovascular disease prediction. JAMA. 2012;307(23):2499–506.

    PubMed  Google Scholar 

  59. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4(3):337–45.

    Article  PubMed  Google Scholar 

  60. Thanassoulis G, Williams K, Ye K, Brook R, Couture P, Lawler PR, et al. Relations of change in plasma levels of LDL-C, non-HDL-C and apoB with risk reduction from statin therapy: a meta-analysis of randomized trials. J Am Heart Assoc. 2014;3(2):e000759.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by Abbott Diagnostic, Akcea, Amgen, Esperion, Novartis, Regeneron, Roche Diagnostic, Sanofi-Synthelabo, NIH, AHA, and ADA. All were paid to institution, not individual.

The following acted as consultants: Abbott Diagnostics, Akcea, Amarin, Amgen, Astra Zeneca*, Boehringer Ingelheim, Denka Seiken, Esperion, Intercept, Janssen, Matinas BioPharma Inc., Merck*, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo* (*significant where noted (> $10,000); remainder modest (< $10,000)).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Salim S. Virani.

Ethics declarations

Conflict of Interest

Anandita Agarwala MD, Jing Liu MD, and Salim S. Virani MD declare that they have no conflict of interest. Dr. Virani was supported by research funding from the Department of Veterans Affairs Health Services Research & Development Service Investigator Initiated Grant, World Heart Federation, and the Jooma and Tahir Family. Dr. Ballantyne was supported by R01-HL134320.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Lipids

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Agarwala, A., Liu, J., Ballantyne, C.M. et al. The Use of Risk-Enhancing Factors to Personalize ASCVD Risk Assessment: Evidence and Recommendations from the 2018 AHA/ACC Multi-Society Cholesterol Guidelines. Curr Cardiovasc Risk Rep 13, 18 (2019). https://doi.org/10.1007/s12170-019-0616-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s12170-019-0616-y

Keywords

Navigation