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Pediatric FH: Screening, Management, and Implementation
Samuel S. Gidding, MDNo COI for this presentation
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Family History + Hypercholesterolemia = FH in Children*
• Cholesterol testing should be used to make a phenotypic diagnosis– > 5 mmol (190 mg/dl)– > 4 mmol and positive family hx (160 mg/dl)– > 3.5 mmol (135 mg/dl) and positive genetic
diagnosis in the family
• Secondary causes ruled out (thyroid, liver, renal, medication, obesity)
• Genetic testing confirms the diagnosis (after parental testing) *FH Foundation
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Algorithm
In press, EHJ
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Impact of Early Treatment of FH on Lifelong LDL-C Exposure
In press, EHJ
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Benefit of Early Treatment of FHon Atherosclerosis Development
In press, EHJ
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Children Treated with Statins Have Lower Event Rates than Their Affected Parents
In press, EHJ
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Pharmacologic Treatment
• Homozygous FH: start treatment at diagnosis For children aged 8-10 years, LDL-C is ideally reduced by 50%
from pre-treatment levels, initially with statins. For children aged ≥ 10 years, especially if there are additional
cardiovascular risk factors, including elevated Lp(a), target LDL-C should be<3.5 mmol/L (130 mg/dL).
Benefits of LDL-C reduction should be balanced against the long-term risk of treatment side effects.
Adherence should be checked if heterozygous FH children fail to achieve LDL-C targets with combination lipid-lowering treatment.
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Developing Evidence for Treating Familial Hypercholesterolemia
• What is the relative benefit of treating to prevent atherosclerosis vs. treating to prevent events? – Treatments and ability to detect atherosclerosis are moving targets over
time. – The time gap between case identification and outcomes (particularly if
treatment is effective) is large• How strong is the Mendelian Randomization evidence?• Can parents be used as historic controls for children?• Are results of cholesterol lowering trials in non-FH patients
relevant?– Provide data on outcomes/safety– Under treat/recognize those chronically exposed
.
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USPSTF Screening Model
LDL-C and Atherosclerosis Imaging
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Subclinical Atherosclerosis ResearchStudy Design
FH Patients get a Subclinical Athero Measure
Test Positive Test Negative
Randomize by treatment intensity
Outcomes Chosen by AgeChange in Subclinical Athero Measure/Events/Cost/Safety are Outcomes
High intensity High intensity Lower intensityLower intensity
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Fig 1 Plots of detection rates against false positive rates for total and LDL cholesterol concentrations according to age in years.
Wald D S et al. BMJ 2007;335:599
©2007 by British Medical Journal Publishing Group
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Screening for FH
• Universal at age 9-11 years– School-based– Office measurement vs lab measurement– Trigger reverse cascade
• Cascade• Opportunistic• EMR/IT strategies
– Labs flag elevated LDL-C as consistent with FH– Data mining
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FH Screening: modeling
Morris JK et al; Am J Med Genet 2011; 158A: 78
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Universal versus selective screening: testing current NCEP guidelines.
Ritchie S K et al. Pediatrics 2010;126:260-265
©2010 by American Academy of Pediatrics
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Reverse CASCADE Screening
• Identify children with FH– LDL cholesterol can be used to discriminate those
with FH and those without in childhood• Identify first degree family members with high
LDL cholesterol• Genotype the parents
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Arguments Against Cholesterol Screening and Treatment in
Childhood • Cost/benefit
– Cost of treating identified cases highly efficient ($5-9K/LY); cost of identifying cases high
• Incremental benefit of identification at age 10 vs 20 years
• Long term side effects of statins• Absence of long term clinical trials with hard
end points
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Barriers to Implementing Cholesterol Screening
• FH awareness• MD
– Belief in preventing early atherogenesis (improving)– Time/skill/reimbursement– Older pts, positive family hx, obesity, high risk conditions increase likelihood of
testing• Family
– Competing health issues– Acceptability– Education– Financial resources– Privacy concerns
• Society– Cost, relative importance, publicity, guideline support
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Homozygous FH
• Patients need to get to specialized centers• Drug trials of newer agents including safety• Role and timing of liver transplantation• Better understanding of natural history
– Atherosclerosis monitoring– Aortic valve disease progression (independent of
LDL lowering)– Phenotype-genotype correlations
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The Pediatric FH Agenda• Screening
– Complete cost effectiveness studies that assess value including years of life gained, universal screening, and reverse cascade screening strategies
– Demonstrate feasibility and acceptability of competing strategies• Management
– Understand the clinical role of subclinical atherosclerosis imaging
– Extend follow up in trials showing event reduction as a result of early intervention
– Measure long term safety including DM, fertility, pregnancy outcomes, muscle toxicity
– Study newer agents, particularly with regard to Safety• Implementation
– Organize care between community and specialist settings– Make FH a reportable disease– Leverage existing organizations to increase FH awareness
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Title Goes Here
• Currently only FH patient registry in the United States
• Hybrid model with patient- and clinician-entered data
• Patients enroll via FH Foundation website– Mobile friendly– Easy to navigate– Give back education to patients i.e. MeTree function
• Initial clinical sites launch in 1st quarter of 2014 (with IRB approval)
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FH should be recognized as a disease where medical treatment of heterozygous forms begins at age 8-10
years and homozygous forms begins at diagnosis
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Additional slides
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NORMAL NEWBORN
RF Exposures:- Environmental- Familial- Lifestyle
Risk factor screening
CHILDREN AT RISK
INTERMEDIATE OUTCOMES: Atherosclerosis Subclinical atherosclerosis End organ injury
LifestyleInterventions
Pharmacologic Interventions
ADULTS AT RISK
Fetal exposures Genetic input
CLINICAL CARDIOVASCULAR DISEASE OUTCOMES:Morbidity Mortality Quality of Life Pediatrics, 2011
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