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

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Presentation on theme: "Weirzbicki, et al BMJ 2008, Aug 27;337:1095 Issue date : August 2008"— Presentation transcript:

1 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 Issue date : August 2008 NICE clinical guideline 71 Developed by the National Collaborating Centre for Primary Car e Identification and management of familial hypercholesterolaemia Royal College General Practictioners Core Team : Kathy DeMott, Leo Nherera, Meeta Kathoria, Beth Shaw, Gill Richie, Vanessa Nunes, Nancy Turnball 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 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,

2 What genes have mutations  FH
Key NICE priorities Diagnosis 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 for GPs NICE evidence-based Guideline  DNA testing is key recommendation What genes have mutations  FH

3 How is cholesterol removed from blood?
LIVER Circulates in blood as LDL particle (“Bad Cholesterol”) “wrapped up” by large protein ApoB Cholesterol used in building membranes of new cells and to make important hormones apoB binds to receptor Liver has special LDL-grabbing protein called a “Receptor” – 7 fingered hand

4 How is cholesterol removed from blood?
LIVER Circulates in blood as LDL particle (“Bad Cholesterol”) “wrapped up” by large protein ApoB Cholesterol used in building membranes of new cells and to make important hormones LDL removed from Blood apoB binds to receptor Liver has special LDL-grabbing protein called a “Receptor” – 7 fingered hand Receptor internalised

5 How is cholesterol removed from blood?
Receptor recycles to surface Recycling controlled by enzyme PCSK9 LIVER LDL degraded and cholesterol  intestine LDL removed from Blood apoB binds to receptor FH - lack of functional receptors, poor LDL binding or high degradation in recycling Most FH due to LDLR mutations, 5% by APOB, 2% PCSK9

6 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 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

7 What about no mutation patients?
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) 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 p < 28.4% 56.3% 25.5% What about no mutation patients?

8 No mutation patients? 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!

9 FH DIAGNOSIS IN FAMILY Y
Chol/TG mmol/l MI age 35yrs 4.4 8.1 Does Dad have FH? Can we find the genetic cause? Can we use this information to see if either son has FH? 4.1 7y 5.4 5y Make a detailed family tree

10 Used DNA techniques to Screen LDLR gene. * Carrier LDLR mutation
CONFIRMING FH DIAGNOSIS IN FAMILY Y 1 * Used DNA techniques to Screen LDLR gene. DNA change Pro664Leu * Carrier LDLR mutation 2 MI 59 Is this true FH ? or is it something else “Familial Combined” Chol/TG mmol/l 7.7/3.5 72y 7.8/1.9 68y 3 4 5 4.4 8.1/1.7 6.7/2.5 8.7/1.6 5.6 Confirm FH, Encourage maintenance of good diet etc Reassure 4.1 7y 5.4 5y FH Carriers ? Using DNA assay None carry mutation 4.5 9y 5.7 6y Average for Children ~4.9. FH > 6.7

11 Open symbol Normal Chol.
GENETIC DIAGNOSIS IN FH FAMILY M 1 2 * Open symbol Normal Chol. Filled symbol High Chol. * Carrier of P644L MI at 29yrs 5.6 43y 9.0 37y * Dietary advice statin later Reassure others N 5 ? Birth 3 4 FH carrier? 4.4 7y 3.1 5y 30th %ile

12 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 % relatives will be FH Mutation -ve families 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 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 Allows unambiguous diagnosis in relatives and for further cascading

13 DNA test avoids false –ve diagnosis
The Overlap Problem Collaboration with John Kastelein et al Amsterdam Data on 2469 non-carriers and 825 carriers of family mutation. Analyse by age 2.2mmol/l Data from Starr et al 2008 4.6mmol/l Gets worse with age! FH False +ve = 8% False –ve = 15% 3.2mmol/l mmol/l DNA test avoids false –ve diagnosis

14 DNA testing for identification of relatives
Starr et al Clin Chem Lab Med 2008 5-15 years 45-54 years 2.2 mMol/l 3.1 mMol/l 4.6 mMol/l 4.6 mMol/l SB SB 4.2mmol/l False +ve = 8%, False –ve = 15% False +ve = 16%, False –ve = 46% As mean LDL-C rises with age in non-FH, overlap increases. DNA testing gives an unambiguous result

15 Cascade Method uses Trained and supported “Genetic Nurses”
LDL-C Diagnostic Tables for 1º relatives 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 Key Likely FH Uncertain Unlikely FH Cascade Method uses Trained and supported “Genetic Nurses” Age 

16 Method used for Cascading
Hadfield et al Ann Clin Chem 2008 A clinical diagnosis of FH is confirmed and a DNA test offered Index case invited to discuss family tracing with FH nurse Family pedigree is drawn and used to identify first degree relatives who should be offered testing Relatives are contacted directly by nurse or via index case Relatives are offered a point-of-care test at the clinic or at home (or are advised to visit their GP for a test) All relatives offered a DNA AND lipid test. When FH suspected GP asked to refer the patient to lipid clinic. Fact File GP to 32 year old sister of FH patient “You’re a young woman you don’t want to be taking tablets for the rest of your life”. Her cholesterol was 9. Need GPs to identify and refer suspect FH and to support CT in relatives.

17 Detection rate using LDL- cut-offs
DH FH Audit and Cascade project 4.5 per Index Case Hadfield et al Ann Clin Chem 2009 2.5 per Index Case 46% under 25 years 66% 60% 36% High acceptance rate, but low pick up of new FH due to out-of-catchment loss & low sensitivity of LDL-C cut-offs

18 Supports acceptance and utility of DNA based-cascade testing.
Improved detection rate in DNA cascade Hadfield et al Ann Clin Chem 2009, Taylor et al Clin Genet in press DH-Cascade based on LDL-C cut-offs 545 index cases  591 relatives tested  211 “FH” 35.7% 1.1 / proband DH-Cascade based on DNA diagnosis 100 index cases  296 relatives tested  166 Mut+ve 2.9 / proband* 56.1%* * p < vs LDL-C arm Supports acceptance and utility of DNA based-cascade testing.

19 NICE Health Economics Modeling of CT
Nehero, Thorogood, Neil, Humphries in prep Compared CT by Cost/QALY £1184 £1463 £1456 £1376 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 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 !

20 Funding now identified for 2009-2010 national roll out
Audit of FH management in UK Humphries, Young, Potter et al On-going through Royal College of Physicians 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 Funding now identified for national roll out

21 Agreed and stable funding streams from commissioners
What do we need for an integrated effective FH Management Programme ? Programme must be a UK-wide Network 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 X X X Agreed and stable funding streams from commissioners

22 Challenge for next 10 years is to find the 100,000 FH patients in UK
FH Research - the Time Line Dequker et al 2004, Medical Archaelogy IMAJ years Madonna Lisa Maria di Gherardini Born Florence 1479 Died age 37 years Xanthelasma? Xanthoma? Challenge for next 10 years is to find the 100,000 FH patients in UK

23 National Register is key NICE recommendation Why a National Register?
Computer and IT needs Hadfield et al DH report 2007 Key Requirements are: 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 a National Register?

24 requires ability to contact
Why is a National Register Needed ? Hadfield et al 2008 Examined in DH FH project On ave 34% 10 rels lived outside catchment area Highest % in London and SE Lowest contact success Efficiency of any CT requires ability to contact distant relatives. DNA testing by postal mouthwash sample

25 What about Screening children?
Proposed by Wald et al BMJ 2007 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 Currently only CT from known adult index cases is tried and tested and demonstrated to be acceptable and cost effective


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