Jonathan Morrell Hastings Key elements of the NICE FH Guideline and the work of the HEART UK FH GIT Jonathan Morrell Hastings

National Health Checks 2009

Banker 31 TC 9.8 HDL 1.4 TG 1.1 Asymptomatic Non-smoker 124/62 Father died MI 49, paternal uncle angina 52, paternal grandfather sudden death 54 2 sons aged 6 and 3 2 brothers and 1 sister TC 9.8 HDL 1.4 TG 1.1

Prevalence of 10 Dyslipidaemias Hypercholesterolaemia Polygenic (common, 1 in 50) Heterozygous FH (HeFH) (approx. 1 in 500) Homozygous FH (HoFH) (approx. 1 in 1,000,000) Hypertriglyceridaemia Familial lipoprotein lipase deficiency (approx. 1 in 1,000,000) Familial apolipoprotein CII deficiency (approx. 1 in 1,000,000) Familial hypertriglyceridaemia (approx. 1 in 100) Combined Hyperlipidaemia Familial combined hyperlipidaemia (approx. 1 in 100) Familial type III hyperlipidaemia (approx. 1 in 5,000)

Same as childhood diabetes How Common is FH ? It is Common - Frequency FH ~1/500 120,000 in UK It is underdiagnosed < 15,000 known, particularly in the < 35 years group (600/14,000 children) Same as childhood diabetes Survey UK Lipid Clinics Missing >85% of predicted Marks, et al 2004 HEARTUK 2008 Neil, et al BMJ 2000

FH – natural history Age (years) ♂ % CHD ♀ <30 5 30-39 22 2 40-49 30-39 22 2 40-49 48 7 50-59 80 51 60-69 100 75 Slack, Lancet.1969;1380-2

Like smoking pack-years LDL- C Burden in FH patients Starr et al 2008 FH patients have high LDL-C from Birth  high LDL-C BURDEN LDL - Burden = LDL-C level x years exposure Like smoking pack-years By 45yrs FH patient has accumulated LDL-C exposure of non- FH 70yr old, explaining high CHD risk and need for aggressive lipid-lowering

Can LDL-C be lowered in FH patients? Hadfield et al 2007 3.3 mmol/l Overall ~ 50% reduction 6.7 mmol/l But 34% > 4.0mmol/l and 12% > 5.0mmol/l n = 249 Low potency (cheap) Simvastatin 40 is inadequate for >95% FH patients Combination therapy may be needed to achieve target

~ 9 years gained by statins Statins reduce CHD in FH Simon Broome UK-FH Register papers, BMJ 1991, Athero 1999, Post Statin 1992–1999 Pre Statin 1988–1992 > 2 fold 20-59 year olds 8.1 = >23 yrs reduction in life expectancy ~ 9 years gained by statins

Current Life Expectancy in treated FH patients Neil et al E Heart J 2008 Age 20-79 years CHD Mortality in those with/without CHD Cancer 1980-91 (14) 1992-06 (76) Total 1980-91 (55) 1992-06 (315) Cancer and Total Mortality Secondary 1980-91 (25) 1992-06 (108) - 25% - 34% Primary 1980-91 (12) 1992-06 (45) - 48% - 29% Based on 2766 (1456 M/1310 F) DFH + PFH patients. 190 CHD and 90 cancer deaths (37727 person years follow-up)

How should we identify people with FH?

Clinical signs Eliza Parachute 1851

Xanthelasma

Corneal Arcus Lipidus

Tendon Xanthomas in HeFH

Simon Broome criteria Definite FH: TC > 6.7 mmol/l or LDL-C >4.0 mmol/l (child <16y) or TC > 7.5 mmol/l or LDL-C >4.9 mmol/l (adult) (levels either pre-treatment or highest on treatment) plus tendon xanthomas in patient, or in 10 relative (parent, sibling, child), or in 20 relative (grandparent, uncle, aunt) or DNA-based evidence of an LDL receptor mutation, familial defective apo B-100, or a PCSK9 mutation. Possible FH is defined as above lipids plus one of: family history of myocardial infarction: below age of 50 years in 20 relative or below age 60 years in 10 relative family history of raised TC >7.5 mmol/l in adult 10 or 20 relative or > 6.7 mmol/l in child or sibling <16y

20 Relatives of FH Proband LDL Cholesterol Distribution UK NEQAS (Birmingham) Roadshows - UK NEQAS on the Web UK NEQAS (Birmingham) Roadshows - UK NEQAS on the Web 14 April 2017 14 April 2017 20 Relatives of FH Proband LDL Cholesterol Distribution Copyright UK NEQAS (Birmingham) - NB! Not all of the slides presented appear in this handout Copyright UK NEQAS (Birmingham) - NB! Not all of the slides presented appear in this handout 18 18

The LDL receptor Brown and Goldstein identified autosomal dominant LDLR defect in FH fibroblasts in 1974

The LDL-receptor pathway ApoB3500 defects (binding ligand). 3-10%. Less severe phenotype LDL receptor defect.80-95% of cases Autosomal recessive hypercholesterolaemia. Rare PCSK9 defect. Gain and loss of function mutations. 2% Soutar, A Nat Clin Pract Cardiovasc Med 2006; 4:214

UCL 2008 Database of published LDLR mutations Leigh et al Annals Hum Genet 2008 1066 different causes of FH reported world-wide www.ucl.ac.uk/ldlr Single base changes + small dels W-Wide n = 949 UK n = 208 * * p = 0.01

NICE FH Guidelines

Key priorities Diagnosis Use the Simon Broome criteria to diagnose FH All individuals should be offered a DNA test to confirm the diagnosis and to assist in cascade testing of relatives CHD risk estimation tools such as those based on the Framingham algorithm should not be used because people with FH are already at a high risk of CHD. In children at risk of FH because of one affected parent the following diagnostic tests should be carried out by age of 10 years : - a DNA test if the family mutation is known - LDL-C measurement if mutation not known

Key priorities Management Ongoing assessment and monitoring Adults - Prescribe a high-intensity statin to achieve a reduction in LDL-C of > 50% from baseline (ie, before treatment). Children/young people – Should be seen by a specialist in an appropriate setting, and using clinical judgement, statin therapy considered by age 10 All people with FH should be offered an annual regular structured review Ongoing assessment and monitoring Cascade testing - combination of DNA testing and LDL-C levels is recommended to identify affected relatives of those with a clinical FH. The use of a nationwide, family-based, follow-up system is recommended to enable comprehensive identification of people affected by FH. Identifying people with FH using cascade testing

Pathway implementation Scotland Wales Northern Ireland England

A guideline not a directive NICE FH Guidelines A guideline not a directive

HEART UK FH Guideline Implementation Team Identify challenges and risks in the implementation of the NICE FH Guideline Propose solutions and incorporate them into a FH Guideline Implementation toolkit Support commissioning and delivery of services

HEART UK FH GIT Raising profile NICE FH Guideline www.heartuk.org.uk/fhgit Influencing commissioning pathway DH, primary care commissioning, RCGP, CV networks and SHAs Support from BHF, PCCS and BCS Identify service gaps (RCP audit) Liaison with NICE Toolkit development

HEART UK FH GIT Anniversary campaign SHA events Consensus meeting Finalise and launch toolkit Patient campaign Lobbying (parliamentary and SHAs) GP survey FOI requests to PCTs Supporting commissioning bids