Post on 06-Feb-2016
description
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