Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: LDLR, APOB, PCSK9
Condition: Heterozygous Familial Hypercholesterolemia
GENEDISEASE PAIRS: LDLR143890 APOB144010 PCSK9603776
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of heterozygous familial hypercholesterolemia (HeFH) is most commonly estimated at 1:200-500, though estimates from 1/67 to 1/1000 have been reported. HeFH has been estimated to affect between 14 and 34 million individuals worldwide.
1 2 3 4 5 6 7 8 9 10 11 12
Clinical Features
(Signs / symptoms)
HeFH is associated with a lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) with levels generally 350-550 mg/dL. The major clinical manifestations of FH result from prolonged exposure to high levels of LDL-C leading to the development of atherosclerotic lesions in the heart, brain, and peripheral arteries. This leads to an increased risk of cardiovascular disease (CVD), most commonly coronary artery disease (CAD). Symptoms of ischemia may occur due the restriction of blood flow; however, acute complications such as myocardial infarction (MI) and sudden cardiac death can occur as the first manifestations of CVD. Other manifestations may include xanthomas around the eyelids and within tendons of the elbows, hands, knees, and feet and corneal arcus.
1 2 3 4 7 8 10 12 13 14
Natural History
(Important subgroups & survival / recovery)
If left untreated, men and women with HeFH typically develop CAD by ages 55 and 60, respectively. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. HeFH patients with tendon xanthomas have higher risk of CVD compared to FH patients without xanthomas (OR=3.20, 95% CI: 2.12-4.82).
1 2 3 4 7 9 10 12 14 15
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
The initial treatment for individuals with FH, irrespective of their calculated cardiovascular risk, should be a high intensity statin with an aim of a reduction of at least 50% in LDL-C concentration from baseline. Statin treatment is lifelong. No studies have examined the use of statins vs placebo in adults with FH. However, high and moderate quality RCTs from populations without FH have found that high-intensity statins reduce non-fatal MI (RR: 0.46, 95% CI: 0.37-0.59). Statins have also been shown to have a small (non-clinically important) effect on reducing 5-year all cause (RR: 0.90, 95% CI: 0.80-1.00), CV mortality (RR: 0.73, 95% CI: 0.61-0.88), and stroke (RR: 0.80, 95% CI: 0.70-0.91). (Tier 1)
6 16
Based on a meta-analysis of 4 observational studies, individuals with HeFH in the pre-statin era exhibited a higher risk for stroke compared with the general population (OR: 7.66, 95% CI: 6.06-9.68, p<0.01) but a lower odds for stroke following the generalization of statin therapy (OR: 0.25, 95% CI: 0.18-0.36, p<0.01). (Tier 1)
1
Ezetimibe monotherapy is recommended as an option for treating primary HeFH in adults in whom initial statin therapy is contraindicated. No trials of ezetimibe in individuals with FH have been published. An RCT (IMPROVE-IT trial) of ezetimibe plus simvastatin vs simvastatin alone in 18,144 patients with stabilized acute coronary syndrome found a 6.4% relative risk reduction at 6 years a composite of cardiovascular death, major coronary event, or non-fatal stroke compared with simvastatin alone (HR: 0.94, 95% CI: 0.89-0.99). (Tier 1)
6 16 17
Adults with FH and contraindications to statin or ezetimibe should be offered a referral to a specialist with expertise in FH for consideration for treatment with either a bile acid sequestrant (resin) or a fibrate. RCTs have found that bile acid sequestrants (2 RCTs, N= 248 with FH) and fibrates (2 RCTs, N= 208 with FH) can results in similar reductions in LDL-C and total cholesterol compared to placebo as treatment with statins. (Tier 1)
6
PCSK9 inhibitors may be considered in HeFH, particularly in patients for whom a statin is contraindicated. (Tier 1)
16
Four RCTs (N=598) found a mean decrease in LDL-C of 8-57% (Alirocumab) and 44-61% (Evolocumab) compared to placebo in HeFH individuals already on a high-dose statin plus ezetimibe in 12 weeks. (Tier 1)
18
Healthcare professionals should offer adults with FH a referral to specialists with expertise in FH and cardiology if they are assessed to be at very high risk of a coronary event base on: established or suspected CHD, family history of premature CHD, or two or more other CV risk factors. (Tier 2)
6 8 19 20
Given that asymptomatic coronary disease may not be detected without routine investigation. In individual instances, an ECG should be considered as a baseline investigation for adults with FH. However, evidence is lacking regarding clinical outcomes based on routine investigation. (Tier 2)
6 9
Lifestyle advice should be provided as a component of medical management, and not a substitute for lipid-modifying drug therapy, including: individualized nutritional advice and physical activity advice, limiting alcohol consumption, stress reduction, and support for weight loss in line with national guidance for the general population. The aim of these interventions is not to lower LDL-C, but to confer a cardioprotective effect. However, there is no evidence that these interventions improve clinical outcomes in adults with FH. (Tier 2)
6 7 8 9 10 12 14 20
Shared care arrangements, to include expertise in cardiology and obstetrics, should be made for women with FH who are considering pregnancy or are pregnant, including: assessment of CHD risk, particularly to exclude aortic stenosis. (Tier 2)
6
Surveillance
All people with FH should be offered a regularly structured review that is carried out at least annual including an update of family pedigree, changes in CHD status of relatives, assessment of any symptoms of CHD, smoking status, fasting lipid profile, discussion about concordance with medication, possible side effects of treatment, and changes in lifestyle or lipid-modifying drug therapy that may be required. (Tier 2)
6
Family Management
No family management recommendations have been provided.
 
Circumstances to Avoid
Individuals with FH should be strongly discouraged from smoking or advised to stop smoking given the greatly increased risk for CHD. (Tier 2)
6 8 10 12
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Codominant
 
Prevalence of Genetic Mutations
Population screening of 50,762 individuals in a US health care system identified pathogenic variants associated with FH in 1:256 in unselected individuals; however, this may be an overestimate as it was based on screening within a single health care delivery system. (Tier 5)
21
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Based on studies of individuals selected based on clinical criteria in the pre-statin era, untreated males are at 50% risk for a fatal or non-fatal coronary event by age 50 years, and women are at 30% risk by 60 years. (Tier 3)
4
Incomplete penetrance is noted for those heterozygous for a APOB pathogenic variant. (Tier 3)
4
Recent findings suggest that only 73% of those with a heterozygous LDLR pathogenic variant have an LDL level >130 mg/dL, suggesting lower penetrance than previously proposed. (Tier 3)
4
While penetrance up to 90% is noted for some pathogenic variants in PCSK9, the penetrance for other PCSK9 pathogenic variants remains largely unknown. (Tier 3)
4
In a US health-system based screening study of individuals with a pathogenic variant associated with FH, 44.7% would have been judged unlikely to have a diagnosis of FH based on Dutch Lipid Clinic Criteria without information about their pathogenic variant. (Tier 5)
21
In a Danish population-based study of patients with FH (selected on clinical criteria) versus non-FH patients, the odds ratios for CAD were 10.3 (95% CI: 7.8–13.8) and 13.2 (95% CI: 10.0–17.4) in subjects treated and not treated with lipid-lowering therapy, respectively. (Tier 1)
13
In an analysis of 12 existing observational studies (N=26,025), individuals high LDL cholesterol (≥190 mg/dl) had six-fold higher risk for CAD (OR: 6.0; 95% CI: 5.2–6.9) compared to those without a high LDL. When limited those with high LDL cholesterol and an FH pathogenic variant, there was a twenty-two-fold increased risk (OR: 22.3; 95% CI: 10.7–53.2). (Tier 3)
4
Within a US health-system based screening study individuals with an FH variant had a higher risk of CAD (OR: 2.6, 95%CI: 2.0-3.5) and premature CAD (OR: 3.7, 95% CI: 2.6 to 5.2). (Tier 5)
21
Expressivity
Despite this high risk of CVD compared with unaffected individuals, the clinical course of atherosclerotic cardiovascular disease in FH subjects is variable. (Tier 4)
12
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions for HeFH include: surveillance (echocardiogram), clinical monitoring, and medication. Statins have possible adverse events of elevated liver enzymes, myopathy, and potential fetal teratogenicity. Adverse reactions with ezetimibe monotherapy are generally gastrointestinal and usually mild, when taken with a statin adverse events may include: elevated liver enzymes, headache, and myalgia. Trials of PCSK9 inhibitors indicate that there is no significant difference in the frequency of adverse events compared to those on placebo.
6 18
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
HeFH is often unrecognized until the inaugural cardiovascular event due to inconsistent screening practices and general unawareness regarding the diagnosis. (Tier 4)
7
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Clinical cardiovascular events / Oral hypercholesterolemia treatment to FH appropriate goal
2
3C
3A
3
11CA
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
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