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

• 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 HyperlipidaemiaFamilial combined hyperlipidaemia (approx. 1 in 100)Familial type III hyperlipidaemia (approx. 1 in 5,000)

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)

How Common is FH ?

Same as childhood diabetes

0

20000

40000

60000

80000

100000

120000

140000

2000 2004 2008 2012 2016 2020

Num

ber

FH k

now

n

Survey UK Lipid Clinics

Missing >85% of predicted

Marks, et al 2004HEARTUK 2008 Neil, et al BMJ 2000

FH – natural history

Age (years)

♂

% CHD

♀

% CHD

<30 5 0

30-39 22 2

40-49 48 7

50-59 80 51

60-69 100 75

Slack, Lancet.1969;1380-2

0

50

100

150

200

250

300

350

0 15 25 35 45 55 65 75

Age (years)

LD

L-C

Bu

rde

n (

mm

ol/

l-y

rs)

FH Non FH

LDL- C Burden in FH patients

By 45yrs FH patient has accumulated LDL-C exposure of non- FH 70yr old, explaining high CHD risk and need for aggressive lipid-lowering

FH patients have high LDL-C from Birth high LDL-C BURDEN

Like smoking pack-years

LDL - Burden = LDL-C level x

years exposure

Starr et al 2008

Can LDL-C be lowered in FH patients?

Low potency (cheap) Simvastatin 40 is inadequate for >95% FH patients

Combination therapy may be needed to achieve target

0%

5%

10%

15%

20%

25%

30%

35%

40%

<2 2-2.9 3-3.9 4-4.9 5-5.9 6-6.9 7-7.9 8-8.9 9-9.9 10-10.9 ≥ 11

LDL (mmol/l)

Pre-treatment LDL Post-treatment LDL

6.7 mmol/l

3.3 mmol/l

Overall~ 50% reduction

n = 249

Hadfield et al 2007

But 34% > 4.0mmol/l and 12% > 5.0mmol/l

Statins reduce CHD in FH

Simon Broome UK-FH Register papers, BMJ 1991, Athero 1999,

8.1 = >23 yrs reductionin life expectancy

~ 9 years gained by statins

3.7

8 .1

8.1

3.7

0 1 2 3 4 5 6 7 8 9 10

Standardised Mortality Ratio

Post Statin1992–1999

Pre Statin1988–1992

> 2 fold

20-59 year olds

Current Life Expectancy in treated FH patients

Neil et al E Heart J 2008

1.03

1.98

3.88

5.15

0 1 2 3 4 5 6

SMR

Secondary

1980-91 (25)

1992-06

(108)

Based on 2766 (1456 M/1310 F) DFH + PFH patients. 190 CHD and 90 cancer deaths (37727 person years follow-up)

Primary

1980-91 (12)

1992-06 (45)

- 25%

CHD Mortality in those with/without CHD

- 48%

- 34%

0.94

1.36

0.63

0.96

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2

SMR

Cancer

1980-91 (14)

1992-06 (76)

Total

1980-91 (55)

1992-06

(315)

Cancer and Total Mortality

- 29%

Age 20-79 years

How should we identify people with FH?

Clinical signs

Eliza Parachute 1851

Xanthelasma

Corneal Arcus Lipidus

Tendon Xanthomas in HeFH

Simon Broome criteriaDefinite 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

or 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

The LDL receptor

Brown and Goldstein

identified autosomal

dominant LDLR defect in FH

fibroblasts in 1974

The LDL-receptor pathway

Soutar, A Nat Clin Pract Cardiovasc Med 2006; 4:214

LDL receptor defect.80-95% of cases

PCSK9 defect. Gain and loss of function mutations. 2%

ApoB3500 defects (binding ligand). 3-10%. Less severe phenotype

Autosomal recessive hypercholesterolaemia. Rare

Leigh et al Annals Hum Genet 2008

0

5

10

15

20

25

P 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Exons of LDLR

Num

ber

Mut

atio

ns (

%)

W-Wide UK

UCL 2008 Database of published LDLR mutations

W-Wide n = 949UK n = 208

*

* p = 0.01

Single base changes+ small dels

1066 different causes of FH reported world-wide www.ucl.ac.uk/ldlr

NICE FH Guidelines

• 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

Diagnosis

Key priorities

• 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.

• 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 reviewIdentifying people with FH using cascade testing

Ongoing assessment and monitoring

Management

Pathway implementation

• Scotland• Wales• Northern Ireland• England

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