Transcript Slide 1

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
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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
Heterozygous FH (HeFH)
Homozygous FH (HoFH)
(common, 1 in 50)
(approx. 1 in 500)
(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
Familial type III hyperlipidaemia
(approx. 1 in 100)
(approx. 1 in 5,000)
How Common is FH ?
It is Common - Frequency FH ~1/500
120,000 in UK
Same as childhood diabetes
It is underdiagnosed < 15,000 known, particularly in the < 35 years
group (600/14,000 children)
Survey UK Lipid Clinics
140000
Number FH known
120000
100000
80000
Missing >85%
of predicted
60000
40000
Marks, et al 2004
HEARTUK 2008
Neil, et al BMJ 2000
20000
0
2000
2004
2008
2012
2016
2020
FH – natural history
Age
(years)
♂
% CHD
♀
% CHD
<30
30-39
40-49
50-59
5
22
48
80
0
2
7
51
60-69
100
75
Slack, Lancet.1969;1380-2
LDL- C Burden in FH patients
Starr et al 2008
FH patients have high LDL-C from Birth  high LDL-C BURDEN
LDL-C Burden (mmol/l-yrs)
FH
Non FH
350
LDL - Burden =
LDL-C level x
years exposure
300
250
200
150
Like smoking
pack-years
100
50
0
0
15
25
35
45
55
65
75
Age (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
Pre-treatment LDL
Post-treatment LDL
3.3 mmol/l
40%
Overall
~ 50% reduction
35%
6.7 mmol/l
30%
25%
20%
15%
But 34% > 4.0mmol/l
and 12% > 5.0mmol/l
10%
5%
0%
<2
2-2.9
n = 249
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)
Low potency (cheap) Simvastatin 40 is inadequate for >95% FH patients
Combination therapy may be needed to achieve target
Statins reduce CHD in FH
Simon Broome UK-FH Register papers, BMJ 1991, Athero 1999,
20-59 year olds
Pre Statin
1988–1992
8.1
> 2 fold
Post
Statin
1992–1999
0
3.7
1
2
3
4
5
6
7
8
9
10
Standardised Mortality Ratio
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
Secondary
1980-91 (25)
5.15
1992-06
(108)
- 25%
Cancer
1980-91 (14)
0.96
1992-06 (76)
- 34%
0.63
3.88
Primary
1980-91 (12)
Total
1980-91 (55)
1.98
- 48%
1992-06 (45)
1
2
3
SMR
1.36
1992-06
(315)
1.03
0
Cancer and Total Mortality
4
5
6
0
- 29%
0.94
0.25
0.5
0.75
1
1.25
1.5
1.75
SMR
Based on 2766 (1456 M/1310 F) DFH + PFH patients. 190 CHD and 90 cancer deaths (37727 person years follow-up)
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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:
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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:
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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
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
W-Wide
Number Mutations (%)
Single base changes
+ small dels
25
www.ucl.ac.uk/ldlr
UK
W-Wide n = 949
UK n = 208
20
15
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10
5
0
P
* p = 0.01
1
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3
4
5
6
7
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9 10 11 12 13 14 15 16 17 18
Exons of LDLR
NICE FH Guidelines
Key priorities
Diagnosis
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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
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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
Ongoing assessment and monitoring
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All people with FH should be offered an annual regular structured
review
Identifying people with FH using cascade testing
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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.
Pathway implementation
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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
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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
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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