1. Pediatric FH: Screening, Management, and Implementation Samuel S. Gidding, MD No COI for this presentation

2. 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

3. Algorithm In press, EHJ

4. Impact of Early Treatment of FH on Lifelong LDL-C Exposure In press, EHJ

5. Benefit of Early Treatment of FH on Atherosclerosis Development In press, EHJ

6. Children Treated with Statins Have Lower Event Rates than Their Affected Parents In press, EHJ

7. 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.

8. 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.

9. USPSTF Screening Model LDL-C and Atherosclerosis Imaging

10. Subclinical Atherosclerosis Research Study Design FH Patients get a Subclinical Athero Measure Test Positive Test Negative Randomize by treatment intensity Outcomes Chosen by Age Change in Subclinical Athero Measure/Events/Cost/Safety are Outcomes High intensity Lower intensity

11. 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

12. 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

13. FH Screening: modeling Morris JK et al; Am J Med Genet 2011; 158A: 78

14. Universal versus selective screening: testing current NCEP guidelines. Ritchie S K et al. Pediatrics 2010;126:260-265 ©2010 by American Academy of Pediatrics

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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 1 st quarter of 2014 (with IRB approval)

21. 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

22. Additional slides

23. NORMAL NEWBORN RF Exposures: - Environmental - Familial - Lifestyle Risk factor screening CHILDREN AT RISK INTERMEDIATE OUTCOMES: Atherosclerosis Subclinical atherosclerosis End organ injury Lifestyle Interventions Pharmacologic Interventions ADULTS AT RISK Fetal exposuresGenetic input CLINICAL CARDIOVASCULAR DISEASE OUTCOMES: Morbidity Mortality Quality of Life Pediatrics, 2011