Guideline Development Group (GDG)GP Chair: Dr Rubin MinhasLead Advisor : Prof Steve HumphriesLipidologists : Prof Andrew Neil, Dr Mary Seed, Dr Ian McDowellNurse Specialist/Genetic Counsellor : Ms Melanie WatsonDietician : Ms Helen Stracey Epidemiologist : Prof Margaret Thorogood Paediatrician : Dr Philip Lee GP : Dr Nadeem Qureshi Patient Representatives : Dawn Davies, Phil RowlandsCo-opted Experts : Tony Weirzbicki, Helen Williams, Aileen Parke, Richard Wray, Mahmoud Barbir, Anneke Lucassen

Royal College General Practictioners Core Team : Kathy DeMott, Leo Nherera, Meeta Kathoria, Beth Shaw, Gill Richie, Vanessa Nunes, Nancy Turnball

Issue date: August 2008

NICE clinical guideline 71 Developed by the National Collaborating Centre for Primary Car e

Identification and management of familial hypercholesterolaemia

http://www.nice.org.uk/nicemedia/pdf/CG071

Weirzbicki, et al BMJ 2008, Aug 27;337:1095

FH Guidelines in Practice : findings from the DH cascade and audit project and the pilot RCP audit

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,

HEARTUK FH Implementation GroupDermot Neely, Jonathan Morrell

• 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 NICE priorities

Key for GPs

Diagnosis

NICE evidence-based Guideline DNA testing is key recommendationWhat genes have mutations FH

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

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

Can detect a mutation in >70% DFH. Current costs ~£400 and falling. Test of single mutation in relative ~ £100. Cholesterol test ~£10, ECG ~£60

0

100

200

300

400

500

UFH PFH DFH

Nu

mb

ers

Mu

t +

ve/-

ve

Mut-ve Mut +ve

p < 0.00001

51 394 190

Some (n=51) did not come with enough information to classify as Definite (n=190) or Possible FH (n=394) – (U-FH)

Detection Rate Data

Completed analysis on 635 proband samples from 6 sites

Conclusions

• Prevalence of PFH ~ twice DFH As seen in Audit

• Significantly higher detection rate in DFH vs PFH As expected from published data

• Sizeable proportion of UFH have mutation

56.3%

28.4%

25.5%

What about no mutation patients?

Taylor et al Clin Genet 2009 in press

No mutation patients?

Technical reasons – No method detects all mutations. Sequencingmay give more complete coverage.

Genetic heterogeneity – May be 4th or 5th gene to be found.

Over-Diagnosis – Many patients do not have “true” FH. Familyhistory of hypercholesterolaemia and early CHD not very specific.

Detection Rate compares favourably with the 20-30% seen inBRCAI/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!

8.1

FH DIAGNOSIS IN FAMILY Y

4.17y

5.45y

4.4

Chol/TGmmol/l

Does Dad have FH?Can we find the genetic cause?

Can we use this information to see if either son has FH?

MI age35yrs

Make a detailed family tree

1

3

2

4

7.7/3.572y

7.8/1.968y

6.7/2.58.1/1.7

CONFIRMING FH DIAGNOSIS IN FAMILY Y

Confirm FH,Encourage

maintenance of good diet etc

Reassure

5

8.7/1.6

4.17y

5.45y

4.59y

5.76y

5.64.4

Chol/TGmmol/l

Is this true FH ? or is

it something else

“Familial Combined”

MI 59

FHFHCarriers ?Carriers ?

Using DNA assay

None carry mutation

*

* *

Used DNA techniques to Screen LDLR gene.

DNA change Pro664Leu

* Carrier LDLR mutation

Average for Children ~4.9. FH > 6.7

1

3

2

4

5.643y

Open symbol Normal Chol.

Filled symbol High Chol.

* Carrier of P644L

9.037y

3.15y

4.47y

*

FHcarrier?

*Dietary advice

statin later

Reassure others

N

5

?Birth

MI at 29yrs

30th %ile

GENETIC DIAGNOSIS IN FH FAMILY M

DNA improves Cost effectiveness of CT

A Mutation identifies best families for cascade testing - Humphries et al 2006

• Mutation +ve probands 50% relatives will be FH

• Mutation -ve families only 25-30% have high cholesterol,

Efficiency of CT based on assumption that 50% of 1st degree relatives will be FH

Allows unambiguous diagnosis in relatives and for further cascading

• CT acceptable and feasible in UK Manchester/Oxford, DH Project, Hadfield et al 2008

• DNA - CT programme running in Netherlands for >10 years - Uman-Eckens et al 2002

• Is Cost Effective in terms of cost per Life years gained Marks et al Humphries BMJ

2000

Those with a detected mutation have higher rate of CHD – Humphries et al 2006

The Overlap Problem

FH

4.44 + 1.43mmol/l

FH vs. Not FH LDL levels, Ages 5-15

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

16.00%

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

Not FH - Histogram

FH - Histogram

Not FH - Normal Dist

FH - Normal Dist

2.2mmol/l

4.6mmol/l

3.2mmol/l

False +ve = 8%False –ve = 15%

Collaboration with John Kastelein et al Amsterdam

Data on 2469 non-carriersand 825 carriers of family mutation. Analyse by age

DNA test avoids false –ve diagnosis

Gets worse with age!

Data from Starr et al 2008

DNA testing for identification of relatives

FH vs. Not FH LDL levels, Ages 5-15

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

16.00%

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

Not FH - Histogram

FH - Histogram

Not FH - Normal Dist

FH - Normal Dist

2.2 mMol/l

4.6 mMol/l

As mean LDL-C rises with age in non-FH, overlap increases.DNA testing gives an unambiguous result

FH vs. Not FH LDL levels, Ages 45-54

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

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

5-15 years 45-54 years

False +ve = 8%, False –ve = 15% False +ve = 16%, False –ve = 46%

3.1 mMol/l

4.6 mMol/l

SB SB

4.2mmol/l

Starr et al Clin Chem Lab Med 2008

LDL-C Diagnostic Tables for 1º relatives

Age

KeyLikely FHUncertain

Unlikely FH

SB LDL-Cut-offs too high for Relatives

• 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”

545

2452

1494990

5912110

500

1000

1500

2000

2500

3000

Index CasesParticipating

LivingRelatives

RelativesContacted

Relatives incatchment

RelativesTested

RelativesDiagnosed with

FH

66%

4.5 per Index Case

60%

36%

2.5 per Index Case

46% under 25 years

Detection rate using LDL- cut-offs

High acceptance rate, but low pick up of new FH due to out-of-catchment loss & low sensitivity of LDL-C cut-offs

Hadfield et al Ann Clin Chem 2009

DH FH Audit and Cascade project

DH-Cascade based on LDL-C cut-offs

545 index cases 591 relatives tested 211 “FH”1.1 / proband

FH Non-FH

35.7%

Mut +ve Mut -ve

DH-Cascade based on DNA diagnosis

100 index cases 296 relatives tested 166 Mut+ve2.9 / proband*

56.1%*

* p < 0.001 vs LDL-C arm

Improved detection rate in DNA cascade

Supports acceptance and utility of DNA based-cascade testing.

Hadfield et al Ann Clin Chem 2009, Taylor et al Clin Genet in press

NICE Health Economics Modeling of CT

1 LDL-Cholesterol only2 DNA only (only CT from mutation +ve probands)3 DNA where mutation plus LDL-C in DFH4 DNA where mutation plus LDL-C in DFH + PFH

Compared CT byCost/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

Nehero, Thorogood, Neil, Humphries in prep

Audit of FH management in UK

On-going through Royal College of Physicians

Funding now identified for 2009-2010 national roll out

Humphries, Young, Potter et al

• 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.

• 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

Key Findings

What do we need for an integrated effective FH Management Programme ?

FH clinics run by Lipidologists

Access to Pediatric input

Trained “Genetic” FH Nurses for Cascade Testing

DNA testing by accredited Genetics Labs

National Register – link families and avoid duplication

Appropriate Computer software and connectivity

Core Data set and agreed Quality Standards

Audit of service

Agreed and stable funding streams from commissioners

Programme must be a UK-wide Network

X

X

X

FH Research - the Time Line

Madonna Lisa Maria di GherardiniBorn Florence 1479Died 1526 age 37 years

Xanthoma?

1503 - 24 years

Xanthelasma?

Dequker et al 2004, Medical Archaelogy IMAJ

Challenge for next 10 years is to find the 100,000 FH patients in UK

Computer and IT needs

Key Requirements are:

Why a National Register?

Hadfield et al DH report 2007

• 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

• 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 is a National Register Needed ?

Efficiency of any CTrequires ability to contact

distant relatives.

Hadfield et al 2008

87%

13%

68%

32%

79%

21%

50%50%

62%

38%

• Examined in DH FH project

• On ave 34% 10 rels lived outside catchment area

• Highest % in London and SE

• Lowest contact success

DNA testing by postal mouthwash sample

Proposed by Wald et al BMJ 2007

What about Screening children?

Currently only CT from known adult index cases is tried and tested and demonstrated to be acceptable and cost effective

• 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.”

• 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

Counter - Hadfield and Humphries BMJ 2007