Can Coronary Artery Calcium Scores Help to Personalize Risk Assessment and Tailor Treatment in Familial Hypercholesterolemia?

Quick Takes

  • 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.

Figure 1

Figure 1


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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

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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