Power of the Pedigree: The Family History Variable for ASCVD Risk Stratification

Quick Takes

  • 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

Summary

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.

References

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  2. Deutscher S, Epstein FH, Kjelsberg MO. Familial aggregation of factors associated with coronary heart disease. Circulation 1966;33:911-24.
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  28. 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.
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Clinical Topics: Dyslipidemia, Prevention, Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Hypertension

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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