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Guideline Development Group (GDG) GP Chair: Dr Rubin Minhas Lead Advisor : Prof Steve Humphries

Issue date. :. August 2008. Identification and. management of familial. hypercholesterolaemia. NICE clinical. guideline. 71. Developed by the National. Collaborating. Centre for Primary Car. e.

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Guideline Development Group (GDG) GP Chair: Dr Rubin Minhas Lead Advisor : Prof Steve Humphries

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  1. Issue date : August 2008 Identification and management of familial hypercholesterolaemia NICE clinical guideline 71 Developed by the National Collaborating Centre for Primary Car e 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 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 : MsMelanie Watson Dietician :MsHelen 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, http://www.nice.org.uk/nicemedia/pdf/CG071

  2. 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. 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

  4. 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 < 0.00001 28.4% 56.3% 25.5% 51 394 190 What about no mutation patients?

  5. 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!

  6. 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

  7. * Used DNA techniques to Screen LDLR gene. DNA change Pro664Leu * Carrier LDLR mutation * * FH Carriers ? CONFIRMING FH DIAGNOSIS IN FAMILY Y 2 1 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 5.6 8.1/1.7 6.7/2.5 8.7/1.6 Confirm FH, Encourage maintenance of good diet etc Reassure 4.1 7y 5.4 5y Using DNA assay None carry mutation 4.5 9y 5.7 6y Average for Children ~4.9. FH > 6.7

  8. * 5 Dietary advice statin later Reassure others ? Birth N GENETIC DIAGNOSIS IN FH FAMILY M Open symbol Normal Chol. Filled symbol High Chol. * Carrier of P644L * 2 1 MI at 29yrs 5.6 43y 9.0 37y 3 4 FH carrier? 4.4 7y 3.1 5y 30th %ile

  9. 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 50% 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

  10. 3.2mmol/l 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% 4.44 + 1.43mmol/l DNA test avoids false –ve diagnosis

  11. 3.1 mMol/l 4.6 mMol/l SB SB 4.2mmol/l DNA testing for identification of relatives Starr et al Clin Chem Lab Med 2008 5-15 years 45-54 years 2.2 mMol/l 4.6 mMol/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

  12. 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 

  13. Detection rate using LDL- cut-offs 46% under 25 years DH FH Audit and Cascade project 4.5 per Index Case Hadfield et al Ann Clin Chem 2009 2.5 per Index Case 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

  14. Improved detection rate in DNA cascade 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 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 Supports acceptance and utility of DNA based-cascade testing.

  15. 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 ! http://www.nice.org.uk/nicemedia/pdf/CG071FullGuidelineAppendixE.pdf

  16. Key Findings • 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 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. Funding now identified for 2009-2010 national roll out

  17. 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

  18. Xanthoma? Xanthelasma? 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 Challenge for next 10 years is to find the 100,000 FH patients in UK

  19. 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 availableand supported • Package being trialled in Wales -Ian McDowell et al • Will report on findings in next 6 months Why a National Register?

  20. 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

  21. Counter - Hadfield and Humphries BMJ 2007 • 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 • 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.” Currently only CT from known adult index cases is tried and tested and demonstrated to be acceptable and cost effective

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