Transcript No Slide Title

FH Guidelines in Practice : findings from the DH cascade
and audit project and the pilot RCP audit
Weirzbicki, et al BMJ 2008, Aug 27;337:1095
Royal College General Practictioners Core Team : Kathy DeMott, Leo Nherera, Meeta
Kathoria, Beth Shaw, Gill Richie, Vanessa Nunes, Nancy Turnball
Issue date : August 2008
Identification and
management of familial
hypercholesterolaemia
Guideline Development Group (GDG)
GP Chair: Dr Rubin Minhas
Lead Advisor : Prof Steve Humphries
Lipidologists : Prof Andrew Neil, Dr Mary Seed, Dr Ian McDowell
Nurse Specialist/Genetic Counsellor : Ms Melanie Watson
Dietician : Ms Helen Stracey
Epidemiologist : Prof Margaret Thorogood
Paediatrician : Dr Philip Lee
GP : Dr Nadeem Qureshi
Patient Representatives : Dawn Davies, Phil Rowlands
Co-opted Experts : Tony Weirzbicki, Helen Williams, Aileen Parke,
Richard Wray, Mahmoud Barbir, Anneke Lucassen
HEARTUK FH Implementation Group
Dermot Neely, Jonathan Morrell
NICE clinical guideline 71
Developed by the National Collaborating Centre for Primary Car e
http://www.nice.org.uk/nicemedia/pdf/CG071
CVG - Ros Whittall, Tina Hubbard, Sarah Leigh, Royal Free Lipid Clinic - Devi Nair
ICH - Gail Norbury, Alison Taylor, Sian Tabrah, Karen Heath,
FH-Audit – Gaye Hadfield, Brian Starr, Mabella Farrer, Gretta Wood
Simon Broome Study Group - Andrew Neil, Gil Thompson, Nigel Capps, Ian McDowell
John Betteridge, Rossi Naoumova, Mary Seed, Paul Durrington,
Key NICE 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.
Key for GPs
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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
NICE evidence-based Guideline  DNA testing is key recommendation
What genes have mutations  FH
DNA tests for FH GOSH Regional DNA lab since 1997
LDLR - >1000 mutations worldwide! (UK ~200)
often need to screen whole gene - EXPENSIVE
~5% have large deletion – need special method
APOB - Only 1 mutation
CHEAP
PCSK9 - Only 1 common mutation
CHEAP
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Fully accredited / Material archived.
Reports sent to GPs/lipidologists within 6 months.
Established mutation web site (www.ucl.ac.uk/fh).
Over last 2 years 635 proband and 296 relative samples
Can detect a mutation in >70% DFH. Current costs ~£400 and falling. Test
of single mutation in relative ~ £100. Cholesterol test ~£10, ECG ~£60
Detection Rate Data
Taylor et al Clin Genet 2009 in press
Completed analysis on 635 proband samples from 6 sites
Some (n=51) did not come with enough information to classify as Definite (n=190) or
Possible FH (n=394) – (U-FH)
Mut-ve
Mut +ve
Conclusions
Numbers Mut +ve/-ve
500
p < 0.00001
• Prevalence of PFH ~ twice DFH
As seen in Audit
400
200
100
0
• Significantly higher detection rate
28.4%
300
in DFH vs PFH
As expected from published data
56.3%
25.5%
51
394
190
UFH
PFH
DFH
What about no mutation patients?
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Sizeable proportion of UFH have
mutation
No mutation patients?
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Technical reasons – No method detects all mutations. Sequencing
may give more complete coverage.
Genetic heterogeneity – May be 4th or 5th gene to be found.
Over-Diagnosis – Many patients do not have “true” FH. Family
history of hypercholesterolaemia and early CHD not very specific.
Detection Rate compares favourably with the 20-30% seen in
BRCAI/2 in familial breast cancer- also fewer “unclassified” variants
Need for pre-test counseling about detection rate
and that non-detection of a mutation does not mean not FH!
FH DIAGNOSIS IN FAMILY Y
Chol/TG
mmol/l
MI age
35yrs
4.4
8.1
4.1
7y
5.4
5y
Make a detailed family tree
Does Dad have FH?
Can we find the genetic cause?
Can we use this information to see if
either son has FH?
CONFIRMING FH DIAGNOSIS IN FAMILY Y
2
1
Chol/TG
mmol/l
7.7/3.5
72y
*MI 59
Used DNA techniques to
Is Screen
this true
FH gene.
? or is
LDLR
7.8/1.9
68y
it something else
DNA change Pro664Leu
“Familial Combined”
* Carrier LDLR mutation
3
4.4
*
8.1/1.7
4.1
7y
5.4
5y
4
5
6.7/2.5
5.6
8.7/1.6
FH assay
Using DNA
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NoneCarriers
carry mutation
Average for Children ~4.9. FH > 6.7
*
4.5
9y
5.7
6y
Confirm FH,
Encourage
maintenance
of good diet etc
Reassure
GENETIC DIAGNOSIS IN FH FAMILY M
2
1
5.6
43y
9.0
37y
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3
FH
carrier?
30th %ile
*MI at 29yrs
4.4
7y
4
Open symbol Normal
Chol.
Filled symbol
High Chol.
* Carrier of P644L
5
3.1
5y
?
Birth
N
Dietary advice
statin later
Reassure others
DNA improves Cost effectiveness of CT
Efficiency of CT based on assumption that 50% of 1st degree relatives will be FH
A Mutation identifies best families for cascade testing - Humphries et al 2006
• Mutation +ve probands
• Mutation -ve families
50% relatives will be FH
only 25-30% have high cholesterol,
Those with a detected mutation have higher rate of CHD – Humphries et al 2006
• CT acceptable and feasible in UK
• DNA - CT programme running in Netherlands for >10 years • Is Cost Effective in terms of cost per Life years gained
Manchester/Oxford, DH Project, Hadfield et al 2008
Uman-Eckens et al 2002
Marks et al Humphries BMJ 2000
Allows unambiguous diagnosis in relatives and for further cascading
The Overlap Problem
Collaboration with John Kastelein et al Amsterdam
FH vs. Not FH LDL levels, Ages 5-15
2.2mmol/l
16.00%
Data from Starr et al 2008
14.00%
Data on 2469 non-carriers
and 825 carriers of family
mutation.
Analyse by age
12.00%
4.6mmol/l
10.00%
Not FH - Histogram
FH - Histogram
Not FH - Normal Dist
FH - Normal Dist
8.00%
FH
6.00%
False +ve = 8%
False –ve = 15%
4.00%
2.00%
Gets worse
with age!
4.44 + 1.43mmol/l
0.00%
0.6
1
1.4
1.8
2.2
2.6
3
3.4
3.8 4.2
4.6
5
5.4 5.8
6.2
6.6
7
7.4
7.8
8.2 8.6
9
LDL mmol/l
3.2mmol/l
DNA test avoids false –ve diagnosis
DNA testing for identification of relatives
Starr et al Clin Chem Lab Med 2008
FH vs. Not FH LDL levels, Ages 45-54
FH vs. Not FH LDL levels, Ages 5-15
5-15 years
45-54 years
12.00%
16.00%
3.1 mMol/l
2.2 mMol/l
14.00%
10.00%
12.00%
4.6 mMol/l
10.00%
8.00%
4.6 mMol/l
Not FH - Histogram
FH - Histogram
Not FH - Normal Dist
FH - Normal Dist
6.00%
8.00%
SB
6.00%
SB
4.00%
4.00%
2.00%
2.00%
0.00%
0.6
1
1.4
1.8
2.2
2.6
3
3.4
3.8
4.2
4.6
5
5.4
5.8
6.2
6.6
7
7.4
7.8
LDL mmol/l
False +ve = 8%, False –ve = 15%
8.2
8.6
9
0.00%
4.2mmol/l
0.6 1 1.4 1.8 2.2 2.6 3 3.4
3.8 4.2 4.6 5 5.4 5.8 6.2 6.6 7 7.4 7.8 8.2 8.6 9
LDL mmol/l
False +ve = 16%, False –ve = 46%
As mean LDL-C rises with age in non-FH, overlap increases.
DNA testing gives an unambiguous result
LDL-C Diagnostic Tables for 1º relatives
SB LDL-Cut-offs too high for Relatives
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Key
Likely FH
Uncertain
Unlikely FH
Age 
Appropriate specificity and sensitivity
for 1/500
In 10 relatives probability = ½
NICE recommends to use diagnostic
chart from Starr et al 2008
Considerable “grey aea” – have to
retest and follow up
Cascade Method uses
Trained and supported
“Genetic Nurses”
Detection rate using LDL- cut-offs
DH FH Audit and Cascade project
3000
4.5 per Index Case
Hadfield et al Ann Clin Chem 2009
2500
2.5 per
Index Case
2000
46% under
25 years
66%
1500
60%
2452
1000
36%
1494
500
990
591
545
211
0
Index Cases
Participating
Living
Relatives
Relatives
Contacted
Relatives in
catchment
Relatives
Tested
Relatives
Diagnosed with
FH
High acceptance rate, but low pick up of new FH due to out-ofcatchment loss & low sensitivity of LDL-C cut-offs
Improved detection rate in DNA cascade
Hadfield et al Ann Clin Chem 2009, Taylor et al Clin Genet in press
FH
Non-FH
DH-Cascade based on LDL-C cut-offs
545 index cases  591 relatives tested  211 “FH”
35.7%
1.1 / proband
Mut +ve
Mut -ve
DH-Cascade based on DNA diagnosis
56.1%*
100 index cases  296 relatives tested  166 Mut+ve
*
2.9 / proband
*p
< 0.001 vs LDL-C arm
Supports acceptance and utility of DNA based-cascade testing.
NICE Health Economics Modeling of CT
Nehero, Thorogood, Neil, Humphries in prep
Compared CT by
1
2
3
4
LDL-Cholesterol only
DNA only (only CT from mutation +ve probands)
DNA where mutation plus LDL-C in DFH
DNA where mutation plus LDL-C in DFH + PFH
Cost/QALY
£1184
£1463
£1456
£1376
Compared to LDL-C only, use of DNA where a mutation can be found
plus using LDL for identification of FH relatives in DFH + PFH gave most QALYs,
with an Incremental Cost Effectiveness Ratio of ~£2700/QALY
Compared to the NICE threshold of £20,000 this is
VERY GOOD VALUE !
http://www.nice.org.uk/nicemedia/pdf/CG071FullGuidelineAppendixE.pdf
Audit of FH management in UK
Humphries, Young, Potter et al
On-going through Royal College of Physicians
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Obtained 1 yr funding from DH
Established Steering group with reps from Colleges/stakeholders
Developed web-based information capture system using NICE recs
Trialled in 14 lipid clinics throughout England and Wales – 248 notes
Reported in June 2008.
Key Findings
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Patient management good
Additional resources will be needed to manage increased numbers
Funding DNA testing not widely available (1/14)
No systematic CT - opportunistic only
Only ad hoc shared care and pediatric arrangements
Funding now identified for 2009-2010 national roll out
What do we need for an integrated effective FH
Management Programme ?
Programme must be a UK-wide Network
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Access to Pediatric input
X
Trained “Genetic” FH Nurses for Cascade Testing
X
DNA testing by accredited Genetics Labs
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National Register – link families and avoid duplication X
Appropriate Computer software and connectivity
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Core Data set and agreed Quality Standards
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Audit of service
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FH clinics run by Lipidologists
Agreed and stable funding streams from commissioners
FH Research - the Time Line
Dequker et al 2004, Medical Archaelogy IMAJ
1503 - 24 years
Madonna Lisa Maria di Gherardini
Born Florence 1479
Died 1526 age 37 years
Xanthoma?
Xanthelasma?
Challenge for next 10 years is to find the 100,000 FH patients in UK
Computer and IT needs
Hadfield et al DH report 2007
Key Requirements are:
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Draws Pedigree
Collects agreed core (clinical and personal) data set
Maintains high level of data confidentiality and security (encryption)
Manages patient pathway (invite/follow up letters, appointments etc)
Compatibility with healthcare IT structures
Enables connectivity across SHA/Devolved province borders.
National Register is key NICE recommendation
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Dutch StOh CT programme have developed a package that achieves this.
Commercially available and supported
Package being trialled in Wales -Ian McDowell et al
Will report on findings in next 6 months
Why a National Register?
Why is a National Register Needed ?
Hadfield et al 2008
32%
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21%
68%
Examined in DH FH project
On ave 34% 10 rels lived outside
catchment area
Highest % in London and SE
Lowest contact success
79%
Efficiency of any CT
requires ability to contact
distant relatives.
13%
87%
50%
50%
DNA testing by postal
mouthwash sample
38%
62%
What about Screening children?
Proposed by Wald et al BMJ 2007
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Screen all children for high cholesterol at the time of childhood immunisation,
Test the parents of the identified children  one with highest Chol has FH
“elegantly screens for FH in two generations simultaneously… with the potential
of preventing premature CHD in nearly everyone with the disorder.”
Counter - Hadfield and Humphries BMJ 2007
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No data on acceptability of the test to parents (and therefore take-up rate)
No data on cost of the programme (and therefore cost- effectiveness)
Overlap in Chol levels of FH and non-FH children is >> than used in model
Currently only CT from known adult index cases is tried and
tested and demonstrated to be acceptable and cost effective