Pediatric FH: Screening, Management, and Implementation

Samuel S. Gidding, MDNo COI for this presentation

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

Algorithm

In press, EHJ

Impact of Early Treatment of FH on Lifelong LDL-C Exposure

In press, EHJ

Benefit of Early Treatment of FHon Atherosclerosis Development

In press, EHJ

Children Treated with Statins Have Lower Event Rates than Their Affected Parents

In press, EHJ

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.

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

.

USPSTF Screening Model

LDL-C and Atherosclerosis Imaging

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

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

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

FH Screening: modeling

Morris JK et al; Am J Med Genet 2011; 158A: 78

Universal versus selective screening: testing current NCEP guidelines.

Ritchie S K et al. Pediatrics 2010;126:260-265

©2010 by American Academy of Pediatrics

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

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

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

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

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

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)

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

Additional slides

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