Power of the Pedigree: The Family History Variable for ASCVD Risk Stratification
- Current prevention guidelines recommend the assessment of family history (FamHx) to guide ASCVD risk prediction, particularly when therapeutic uncertainty exists.
- A validated FamHx is an inexpensive, clinical risk factor that imparts a higher lifetime risk for future ASCVD events and should signal the investigation and treatment of other risk factors.
- The use of coronary artery calcium (CAC) testing can influence the shared decision making process after consideration of risk enhancing factors such as FamHx; however, even in the absence of CAC, statin pharmacotherapy is recommended to those with a strong FamHx.
Assessment of family history (FamHx) of coronary heart disease is an inexpensive and evidence-based tool to refine atherosclerotic cardiovascular disease (ASCVD) risk estimation and guide decisions regarding preventive therapies.1 A cornerstone of cardiovascular risk evaluation is the patient history, of which FamHx represents both the development of ASCVD as a result of inherited vulnerabilities (genetics) and behaviors often embedded in close social structures, such as tobacco use, as well as dietary and exercise habits (environment).1,2
Prospective data have consistently demonstrated an association between FamHx and risk of future coronary heart disease (CHD), ranging from 1.5-2.0-fold higher risk, independent of conventional risk factors.3 FamHx has been incorporated into some conventional risk prediction algorithms such as the Reynolds risk score, PROCAM, and QRISK.4-6 Alternatively, adoption of FamHx into guideline endorsed risk prediction models, such as the American ASCVD Risk Estimator and European SCORE algorithm has been limited.7-9 This is likely because FamHx is a non-modifiable risk factor subject to reporting errors/misclassification bias; it has limited additive predictive on top of established risk factors and risk scores, and has varied temporal association in relation to incident ASCVD events (i.e. greater influence of genetic component for premature events, and a more balanced contribution of acquired CVD risk factors for later onset events).1,10
Use of Family History Pertaining to the Management of Blood Cholesterol
The 2018 Multisociety Guideline on the Management of Blood Cholesterol recommend assessment of ASCVD risk using the Pooled Cohorts Equations (PCE) among those aged 40-75 years of age with an LDL-C ≥70 mg/dL and <190 mg/dL, and free of ASCVD and diabetes mellitus.11 For those who are classified as borderline (5% - <7.5%) or intermediate (≥7.5% - 20%) risk, a patient-clinician discussion is suggested to identify ASCVD risk enhancing factors (RENF) such as FamHx, which would otherwise favor the initiation of a moderate intensity statin when present. The presence of a validated FamHx likely imparts a greater lifetime ASCVD-risk.3,11
The 2018 guideline recommends the use of a FamHx of premature-ASCVD, traditionally defined as the presence of a familial ASCVD event occurring in males before the age of 55 years and/or females before 65 years.11,12 The use of any first-degree relative with ASCVD (mother, father, sibling) may perform just as well as the assessment of premature FamHx in predicting ASCVD-events (HR, 95%CI): 1.28 (1.10-1.49) and 1.29 (1.07-1.55), respectively.1 The presence of FamHx of premature ASCVD can be clinically significant among young adults with persistent, moderate hypercholesterolemia (LDL-C 160-189 mg/dL) and would likely influence statin initiation given the increased probability of familial hypercholesterolemia.11,13
FamHx is the only clinical risk factor that independently improves discrimination and reclassification of ASCVD when added to traditional Framingham risk factors.1,14,15 In a study comparing risk markers using diagnostic likelihood ratios (models the change in individual risk), the absence of any-FamHx resulted in the greatest downward shift in estimated ASCVD risk among clinical risk factors.16 The absence of any-FamHx also resulted in the largest downward risk reclassification (i.e. "de-risking") to post-test risk <7.5% among non-imaging risk factors such as hsCRP <2 mg/dL, homocycteine <10 μmol/L, and NT-proBNP <100 pg/ml (net reclassification index (%): 3.61, 1.68, 1.38, and 1.21, respectively).16 In a sex-specific subgroup analysis of the JUPITER study, rosuvastatin therapy significantly reduced the risk of ASCVD events among women without a FamHx, but more so in the presence of a FamHx [(HR, 95%CI): 0.20 (0.06-0.69) and 0.63 (0.41-0.96)] though there was no statistically significant interaction by FamHx (p-interaction=0.07).17
Use of Coronary Artery Calcium to Further Refine Risk
In the context of the patient-clinician discussion, if a decision about statin therapy remains unclear, quantification of coronary artery calcium (CAC) can be considered as a decision aid for additional risk reclassification. A CAC score of 1-99 would favor starting statin therapy, particular in those aged ≥55 years.10,11
A CAC score of >100 typically correlates with a 10-year-ASCVD-risk of ≥7.5%, which is an accepted threshold for statin initiation.18 Given that a CAC score of zero (CAC=0) indicates low ASCVD risk for the subsequent 10 years, statin therapy can be safely deferred in the presence of RENF, with the exception of those with diabetes mellitus, active tobacco users, or those with a FamHx.11,12,19
The rationale for the current recommendation that CAC scanning should not be pursued in those with a FamHx is that these individuals remain at modest risk of ASCVD events even in the absence of detectable CAC.11,12,20-23 This observed higher risk due to FamHx may be driven by a higher likelihood of the presence of non-calcified plaque or accelerated atherosclerosis (i.e. a shorter "warranty period" for CAC=0).20,21
The selective use of CAC can be considered in low-risk individuals (PCE <5%) with a strong FamHx of premature ASCVD.24 Since the PCE is highly reliant on age, young patients are unlikely to have a high estimated risk score, even in the presence of traditional risk factors. The presence of CAC (CAC >0) might indicate a group for whom the potential benefit for statin therapy might exceed the potential for adverse side effects.11,12,25-27 Among those with FamHx, elevated biomarkers such as lipoprotein(a) (Lp(a)) and apolipoprotein B (apoB) may also be useful to identify high-risk patients.11,28,29
Risk assessment in primary ASCVD prevention seeks to identify patients who are more likely to benefit from pharmacologic interventions. This assessment includes genetic predisposition, social habits, and environmental factors that increase a patient's vulnerability to the development of disease. The presence of a FamHx of premature ASCVD should prompt the investigation and more aggressive management of other risk factors such as hypertension, dyslipidemia, and diabetes.
Risk assessment should start with the assessment of traditional cardiovascular risk factors and calculation of the 10-year risk of ASCVD with the PCE. Among those at borderline and intermediate ASCVD-risk, the presence of a FamHx of premature-ASCVD may identify higher risk patients, supporting a decision to initiate or intensify statin pharmacotherapy. For low-risk FamHx patients, the presence of CAC more so than biomarkers (Lp(a) and apoB), can further refine risk to guide the clinician-patient risk discussion to patients for whom preventive pharmacotherapy may be useful.
- Patel J, Al Rifai M, Scheuner MT, et al. Basic vs more complex definitions of family history in the prediction of coronary heart disease: the multi-ethnic study of atherosclerosis. Mayo Clin Proc 2018;93:1213-23.
- Deutscher S, Epstein FH, Kjelsberg MO. Familial aggregation of factors associated with coronary heart disease. Circulation 1966;33:911-24.
- Lloyd-Jones DM, Nam BH, D'Agostino RB Sr, 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;291:2204-11.
- Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women. JAMA 2007;297:611-19.
- Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Münster (PROCAM) study. Circulation 2002;105:310-15.
- Hippisley-Cox J, Coupland C, Brindle P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study. BMJ 2017;357:j2099.
- D'Agostino RB Sr, Grundy S, Sullivan LM, Wilson P. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001;286:180–87.
- Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk. Circulation 2013;129:S49-73.
- Thomsen T. HeartScore®: a new web-based approach to European cardiovascular disease risk management. Eur J Cardiovasc Prev Rehabil 2005;12:424-26.
- Khoury MJ, Flanders WD. Bias in using family history as a risk factor in case control studies of disease. Epidemiology 1995;6:511–19.
- 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:e285-e350.
- Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:1376-1414.
- Domanski M, Lloyd-Jones DM, Fuster V, Grundy S. Can we dramatically reduce the incidence of coronary heart disease? Nat Rev Cardiol 2011;8:721-25.
- Yeboah J, Young R, McClelland RL, et al. Utility of nontraditional risk markers in atherosclerotic cardiovascular disease risk assessment. J Am Coll Cardiol 2016;67:139-47.
- Yeboah J, Polonsky TS, Young R, et al. Utility of non-traditional risk markers in individuals ineligible for statin therapy according to the 2013 ACC/AHA cholesterol guidelines. Circulation 2015;132:916-22.
- Blaha MJ, Cainzos-Achirica M, Greenland P, et al. Role of coronary artery calcium score of zero and other negative risk markers for cardiovascular disease: the multi-ethnic study of atherosclerosis (MESA). Circulation 2016;133:849-58.
- Mora S, Glynn RJ, Hsia J, et al. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069-77.
- Budoff MJ, Young R, Burke G, et al. Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J 2018;39:2401-08.
- Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol 2015;66:1657-68.
- Cohen R, Budoff M, McClelland RL, et al. Significance of a positive family history for coronary heart disease in patients with a zero coronary artery calcium score (from the multi-ethnic study of atherosclerosis). Am J Cardiol 2014;114:1210-14.
- Pandey AK, Blaha MJ, Sharma 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 2014;232:369-76.
- Paixao ARM, Berry JD, Neeland IJ, et al. Coronary artery calcification and family history of myocardial infarction in the Dallas heart study. JACC Cardiovasc Imaging 2014;7:679-86.
- Patel J, Al Rifai M, Blaha MJ, et al. Coronary artery calcium improves risk assessment in adults with a family history of premature coronary heart disease: results from multi-ethnic study of atherosclerosis. Circ Cardiovasc Imaging 2015;8:e003186.
- Hecht H, Blaha MJ, Berman DS, et al. Clinical indications for coronary artery calcium scoring in asymptomatic patients: expert consensus statement from the Society of Cardiovascular Computed Tomography. J Cardiovasc Comput Tomogr 2017;11:157-68.
- 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.
- Taylor AJ, Cerqueira M, Hodgson JM, et al. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2010;56:e525-e555.
- Tota-Maharaj R, Blaha MJ, McEvoy JW, et al. Coronary artery calcium for the prediction of mortality in young adults <45 years old and elderly adults >75 years old. Eur Heart J 2012;33:2955-62.
- Mehta A, Virani SS, Ayers CR, et al. Lipoprotein(a) and family history predict cardiovascular disease risk. J Am Coll Cardiol 2020;76:781-93.
- Wiesbauer F, Blessberger H, Azar D, et al. Familial-combined hyperlipidemia in very young myocardial infarction survivors (< or =40 years of age). Eur Heart J 2009;30:1073-79.
Keywords: Primary Prevention, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Calcium, Cardiovascular Diseases, C-Reactive Protein, Cholesterol, LDL, Tobacco Use, Coronary Vessels, Hyperlipoproteinemia Type II, Lipoprotein(a), Hypercholesterolemia, Apolipoproteins B, Genetic Predisposition to Disease, Prospective Studies, Risk Factors, Atherosclerosis, Risk Assessment, Diabetes Mellitus, Coronary Disease, Hypertension, Biological Markers, Algorithms, Decision Support Techniques
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