Can Coronary Artery Calcium Scores Help to Personalize Risk Assessment and Tailor Treatment in Familial Hypercholesterolemia?
- Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic conditions associated with premature atherosclerotic cardiovascular disease (ASCVD) and is vastly underdiagnosed and undertreated.
- Heterogeneity in ASCVD risk in patients with HeFH suggests an opportunity and need to tailor the treatment strategy using clinical data beyond LDL-C.
- CAC testing may be able to further clarify the heterogeneity in ASCVD risk among FH patients and identify those who would derive the largest benefit from non-statin therapies.
Heterozygous familial hypercholesterolemia (HeFH) affects approximately one in 250 Americans, making it one of the most common genetic conditions associated with premature atherosclerotic cardiovascular disease (ASCVD).1 There is a substantial increase in mortality from coronary artery disease (CAD) related to LDL-C exposure in individuals with HeFH compared to those without, especially in young adults,2 and risk is also increased in those with the familial hypercholesterolemia phenotype (defined as LDL-C ≥190 mg/dL).3
Heterogeneity in HeFH
HeFH patients vary in genotype, phenotype, and response to treatment. The Spanish Familial Hypercholesterolemia Cohort Study (SAFEHEART) study documented 209 functional mutations in the LDL receptor (LDLR) and apolipoprotein B (apoB) genes in over 2,000 individuals,4 and, despite a high lifetime risk, cardiovascular risk varies in HeFH, even among those with the same mutation.1,5 Genetic background, lifestyle factors, and comorbidities likely contribute to this heterogeneity in risk.
Statin therapy in HeFH has led to a halving in risk of fatal CAD events.6,7 American guidelines recommend lifestyle modifications and high-intensity statin treatment in individuals with HeFH with the initial goal to reduce LDL-C by at least 50% and achieve an LDL-C of <100 mg/dL (in the absence of CAD or other major risk factors) or ≤70 mg/dL (in the presence of CAD or other major risk factors).8,9 Recent European guidelines are even more aggressive and recommend lowering LDL-C to ≤55 mg/dL.10
Even with statin treatment, those with HeFH have high odds of developing ASCVD compared to those without.11,12 Moreover, studies have shown difficulty in optimizing LDL-C levels with statin monotherapy in individuals with HeFH.13,14 Many of those with HeFH would benefit from non-statin therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, access barriers have limited their use, and a "one-size fits all" approach to primary prevention is likely not clinically desirable or cost-effective.15
In terms of assessing risk in HeFH and directing more intensive treatment to those patients most likely to benefit, there is no current consensus on risk stratification tools. Current guidelines recommend against using common risk calculators like the Pooled-Cohort Equation and Framingham Risk Score in patients with HeFH. While scoring systems for HeFH risk (e.g. SAFEHEART-RE) are being developed and show promise, none have been validated.4 The heterogeneity in the clinical course of HeFH, coupled with difficulty in achieving guideline-directed LDL-C levels, may present an opportunity for personalizing therapy.
Potential for Personalization of FH Care with CAC
Coronary Artery Calcium (CAC) has emerged as a tool in personalized risk assessment in the general population. European and American guidelines have given CAC a class IIa recommendation for intermediate-risk or selected borderline-risk adults if the decision about statin use remains uncertain.9,16
A CAC of zero has been shown to be one of the strongest negative risk markers of ASCVD events over 5-15 years in the general population as well as in those with diabetes.17-21 The absence of coronary calcium confers a low 10-year risk for future ASCVD events in individuals considered at high-risk by clinical risk scores and confers better survival in individuals at low-to-intermediate risk.22,23
Similarly, CAC=0 has been applied to individuals with LDL-C ≥190 mg/dL. A recent MESA analysis showed prognostic benefit in individuals with LDL-C ≥190 mg/dL (that is, FH phenotype; most such individuals do not have HeFH).24 Moreover, a study of 206 Brazilians with genetically proven HeFH showed the annualized rates of events per 1,000 individuals for CAC scores of 0 was 0 over a short mean follow-up of 3.4 years.25
HeFH is a common condition that is underdiagnosed and undertreated. A huge clinical priority is to find these patients, cascade screen their families, and initiate proper guideline directed care, including lifestyle modification and high-intensity statin therapy. A >50% LDL-C reduction and attainment of LDL-C <100 mg/dL at a minimum is necessary for primary prevention in HeFH patients.
Many HeFH patients will benefit from further intensification of therapy with non-statins, with ezetimibe and PCSK9 inhibitors highlighted in recent guidelines, bile acid sequestrants historically used, and bempedoic acid now available. In determining treatment strategies (in partnership with the patient), there is an opportunity to take into account personal preferences, clinical risk factors, on-treatment LDL-C, and, potentially, to consider subclinical atherosclerosis imaging to tailor treatment and increase the cost-effectiveness of care of this hetergenous disease.
CAC derived vascular age has improved ASCVD risk discrimination in other populations, and it may have a role in primary prevention for HeFH patients as well. CAC testing may be able to aid in identifying those who likely would and would not derive the largest benefit from further intensification of therapy with non-statin agents. Furthermore, CAC could be a useful tool in shared decision making when a patient with HeFH is uncertain about intensifying therapy in patients without known ASCVD (Figure 1). Therefore, in selected cases, CAC may be a tool that enables patients and clinicians to better partner in the care of HeFH.
- Santos RD, Gidding SS, Hegele RA, et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol 2016;4:850-861.
- Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ 1991;303:893–96.
- Perak AM, Ning H, de Ferranti SD, Gooding HC, Wilkins JT, Lloyd-Jones DM. Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype. Circulation 2016;134:9-19.
- Pérez de Isla L, Alonso R, Mata N, et al. Predicting cardiovascular events in familial hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study). Circulation 2017;135:2133-44.
- Mszar R, Grandhi GR, Valero-Elizondo J, et al. Absence of coronary artery calcification in middle-aged familial hypercholesterolemia patients without atherosclerotic cardiovascular disease. JACC Cardiovasc Imaging 2020;13:1090-92.
- Neil A, Cooper J, Betteridge J, et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J 2008;29:2625-33.
- Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long-term cohort study. BMJ 2008;337:a2423.
- Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 2015;132:2167-92.
- 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: executive summary: 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.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-188.
- Wong B, Kruse G, Kutikova L, Ray KK, Mata P, Bruckert E. Cardiovascular disease risk associated with familial hypercholesterolemia: a systematic review of the literature. Clin Ther 2016;38:1696-1709.
- Masana L, Zamora A, Plana N, et al. Incidence of cardiovascular disease in patients with familial hypercholesterolemia phenotype: analysis of 5 years follow-up of real-world data from more than 1.5 million patients. J Clin Med 2019;8:1080.
- Perez de Isla L, Alonso R, Watts GF, et al. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-Year SAFEHEART registry follow-up. J Am Coll Cardiol 2016;67:1278-85.
- Duell PB, Gidding SS, Andersen RL, et al. Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry. Atherosclerosis 2019;289:85-93.
- Institute for Clinical and Economic Review. Alirocumab for Treatment of High Cholesterol: Effectiveness and Value. New Evidence Update. 2019. Available at: https://icer-review.org/wp-content/uploads/2019/02/ICER_Alirocumab_Final_NEU_021519.pdf . Accessed 11/01/2020.
- Piepoli MF, Abreu A, Albus C, et al. Update on cardiovascular prevention in clinical practice: a position paper of the European Association of Preventive Cardiology of the European Society of Cardiology. Eur J Prev Cardiol 2020;27:181-205.
- Blaha MJ, Blankstein R, Nasir K. Coronary artery calcium scores of zero and establishing the concept of negative risk factors. J Am Coll Cardiol 2019;74:12-14.
- 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.
- Grandhi GR, Mirbolouk M, Dardari ZA, et al. Interplay of coronary artery calcium and risk factors for predicting CVD/CHD mortality: The CAC Consortium. JACC Cardiovasc Imaging 2020;13:1175-86.
- Carr JJ, Jacobs DR Jr, Terry JG, et al. Association of coronary artery calcium in adults aged 32 to 46 years with incident coronary heart disease and death. JAMA Cardiol 2017;2:391-99.
- Valenti V, Hartaigh BÓ, Cho I, et al. Absence of coronary artery calcium identifies asymptomatic diabetic individuals at low near-term but not long-term risk of mortality: a 15-year follow-up study of 9715 patients. Circ Cardiovasc Imaging 2016;9:e003528.
- Nasir K, Rubin J, Blaha MJ, et al. Interplay of coronary artery calcification and traditional risk factors for the prediction of all-cause mortality in asymptomatic individuals. Circ Cardiovasc Imaging 2012;5:467-73.
- Valenti V, Ó Hartaigh B, Heo R, et al. A 15-year warranty period for asymptomatic individuals without coronary artery calcium: a prospective follow-up of 9,715 individuals. JACC Cardiovasc Imaging 2015;8:900-09.
- Sandesara PB, Mehta A, O'Neal WT, et al. Clinical significance of zero coronary artery calcium in individuals with LDL cholesterol ≥190 mg/dL: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2020;292:224-29.
- Miname MH, Bittencourt MS, Moraes SR, et al. Coronary artery calcium and cardiovascular events in patients with familial hypercholesterolemia receiving standard lipid-lowering therapy. JACC Cardiovasc Imaging 2019;12:1797-1804.
Keywords: Dyslipidemias, Hyperlipoproteinemia Type II, Calcium, Coronary Artery Disease, Cholesterol, LDL, Cost-Benefit Analysis, PCSK9 protein, human, Proprotein Convertase 9, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiovascular Diseases, Apolipoproteins B, Factor IX, Factor V
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