Key elements of the NICE FH Guideline and the work of the HEART UK FH GIT
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Transcript of Key elements of the NICE FH Guideline and the work of the HEART UK FH GIT
Key elements of the NICE FH Guideline and the work of the HEART UK FH GIT
Jonathan MorrellHastings
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
HypercholesterolaemiaPolygenic (common, 1 in 50)Heterozygous FH (HeFH) (approx. 1 in 500)Homozygous FH (HoFH) (approx. 1 in 1,000,000)
HypertriglyceridaemiaFamilial 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 F
H 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 5 030-39 22 240-49 48 750-59 80 5160-69 100 75
Slack, Lancet.1969;1380-2
050
100150200250300350
0 15 25 35 45 55 65 75
Age (years)
LDL-
C B
urde
n (m
mol
/l-yr
s)
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/lOverall
~ 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 Goldsteinidentified autosomaldominant LDLR defect in FHfibroblasts 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 M
utat
ions
(%)
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