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;337:1095Issue date:August 2008NICE clinicalguideline71Developed by the NationalCollaboratingCentre for Primary CareIdentification andmanagement of familialhypercholesterolaemiaRoyal College General Practictioners Core Team : Kathy DeMott, Leo Nherera, Meeta Kathoria, Beth Shaw, Gill Richie, Vanessa Nunes, Nancy TurnballGuideline 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 StraceyEpidemiologist : Prof Margaret ThorogoodPaediatrician : Dr Philip LeeGP : Dr Nadeem QureshiPatient Representatives : Dawn Davies, Phil RowlandsCo-opted Experts : Tony Weirzbicki, Helen Williams, Aileen Parke,Richard Wray, Mahmoud Barbir, Anneke LucassenHEARTUK FH Implementation GroupDermot Neely, Jonathan MorrellCVG - Ros Whittall, Tina Hubbard, Sarah Leigh, Royal Free Lipid Clinic - Devi NairICH - Gail Norbury, Alison Taylor, Sian Tabrah, Karen Heath,FH-Audit – Gaye Hadfield, Brian Starr, Mabella Farrer, Gretta WoodSimon Broome Study Group - Andrew Neil, Gil Thompson, Nigel Capps, Ian McDowellJohn Betteridge, Rossi Naoumova, Mary Seed, Paul Durrington,
2 What genes have mutations FH Key NICE prioritiesDiagnosisUse the Simon Broome criteria to diagnose FHAll individuals should be offered a DNA test to confirm the diagnosis and to assistin Cascade testing of relativesCHD risk estimation tools such as those based on the Framingham algorithmshould 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 diagnostictests should be carried out by age of 10 years :- a DNA test if the family mutation is known- LDL-C measurement if mutation not knownKey for GPsNICE evidence-based Guideline DNA testing is key recommendationWhat genes have mutations FH
3 How is cholesterol removed from blood? LIVERCirculates in blood as LDL particle (“Bad Cholesterol”)“wrapped up” by large protein ApoBCholesterol used inbuilding membranes ofnew cells and tomake important hormonesapoB bindsto receptorLiver has special LDL-grabbing proteincalled a “Receptor” – 7 fingered hand
4 How is cholesterol removed from blood? LIVERCirculates in blood as LDL particle (“Bad Cholesterol”)“wrapped up” by large protein ApoBCholesterol used inbuilding membranes ofnew cells and tomake important hormonesLDL removedfrom BloodapoB bindsto receptorLiver has special LDL-grabbing proteincalled a “Receptor” – 7 fingered handReceptor internalised
5 How is cholesterol removed from blood? Receptorrecyclesto surfaceRecycling controlledby enzyme PCSK9LIVERLDL degradedand cholesterol intestineLDL removedfrom BloodapoB bindsto receptorFH - lack of functional receptors, poor LDL binding or high degradation in recyclingMost 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 methodAPOB - Only 1 mutation CHEAPPCSK9 - Only 1 common mutation CHEAPFully 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 samplesCan 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 DataTaylor et al Clin Genet 2009 in pressCompleted analysis on 635 proband samples from 6 sitesSome (n=51) did not come with enough information to classify as Definite (n=190) or Possible FH (n=394) – (U-FH)ConclusionsPrevalence of PFH ~ twice DFHAs seen in AuditSignificantly higher detection ratein DFH vs PFHAs expected from published dataSizeable proportion of UFH havemutationp <28.4%56.3%25.5%What about no mutation patients?
8 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” variantsNeed for pre-test counseling about detection rateand that non-detection of a mutation does not mean not FH!
9 FH DIAGNOSIS IN FAMILY Y Chol/TGmmol/lMI age35yrs4.48.1Does Dad have FH?Can we find the genetic cause?Can we use this information to see if either son has FH?4.17y5.45yMake a detailed family tree
10 Used DNA techniques to Screen LDLR gene. * Carrier LDLR mutation CONFIRMING FH DIAGNOSIS IN FAMILY Y1*Used DNA techniques to Screen LDLR gene.DNA change Pro664Leu* Carrier LDLR mutation2MI 59Is this true FH ? or isit something else“Familial Combined”Chol/TGmmol/l7.7/3.572y7.8/1.968y3454.48.1/1.76.7/2.58.7/1.65.6Confirm FH,Encouragemaintenanceof good diet etcReassure4.17y5.45yFHCarriers ?Using DNA assayNone carry mutation4.59y5.76yAverage for Children ~4.9. FH > 6.7
11 Open symbol Normal Chol. GENETIC DIAGNOSIS IN FH FAMILY M12*Open symbol Normal Chol.Filled symbolHigh Chol.* Carrier of P644LMI at 29yrs5.643y9.037y*Dietary advicestatin laterReassure othersN5?Birth34FHcarrier?4.47y3.15y30th %ile
12 DNA improves Cost effectiveness of CT Efficiency of CT based on assumption that 50% of 1st degree relatives will be FHA Mutation identifies best families for cascade testing - Humphries et al 2006Mutation +ve probands % relatives will be FHMutation -ve families only 25-30% have high cholesterol,Those with a detected mutation have higher rate of CHD – Humphries et al 2006CT acceptable and feasible in UK Manchester/Oxford, DH Project, Hadfield et al 2008DNA - CT programme running in Netherlands for >10 years - Uman-Eckens et al 2002Is Cost Effective in terms of cost per Life years gained Marks et al Humphries BMJ 2000Allows unambiguous diagnosis in relatives and for further cascading
13 DNA test avoids false –ve diagnosis The Overlap ProblemCollaboration with John Kastelein et al AmsterdamData on 2469 non-carriersand 825 carriers of family mutation.Analyse by age2.2mmol/lData from Starr et al 20084.6mmol/lGets worsewith age!FHFalse +ve = 8%False –ve = 15%3.2mmol/lmmol/lDNA test avoids false –ve diagnosis
14 DNA testing for identification of relatives Starr et al Clin Chem Lab Med 20085-15 years45-54 years2.2 mMol/l3.1 mMol/l4.6 mMol/l4.6 mMol/lSBSB4.2mmol/lFalse +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 relativesSB LDL-Cut-offs too high for RelativesAppropriate specificity and sensitivityfor 1/500In 10 relatives probability = ½NICE recommends to use diagnosticchart from Starr et al 2008Considerable “grey aea” – have toretest and follow upKeyLikely FHUncertainUnlikely FHCascade Method uses Trained and supported “Genetic Nurses”Age
16 Method used for Cascading Hadfield et al Ann Clin Chem 2008A clinical diagnosis of FH is confirmed and a DNA test offeredIndex case invited to discuss family tracing with FH nurseFamily pedigree is drawn and used to identify first degree relatives who should be offered testingRelatives are contacted directly by nurse or via index caseRelatives 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 FileGP 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 project4.5 per Index CaseHadfield et al Ann Clin Chem 20092.5 perIndex Case46% under25 years66%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 cascadeHadfield et al Ann Clin Chem 2009, Taylor et al Clin Genet in pressDH-Cascade based on LDL-C cut-offs545 index cases 591 relatives tested 211 “FH”35.7%1.1 / probandDH-Cascade based on DNA diagnosis100 index cases 296 relatives tested 166 Mut+ve2.9 / proband*56.1%** p < vs LDL-C armSupports acceptance and utility of DNA based-cascade testing.
19 NICE Health Economics Modeling of CT Nehero, Thorogood, Neil, Humphries in prepCompared CT byCost/QALY£1184£1463£1456£1376LDL-Cholesterol onlyDNA only (only CT from mutation +ve probands)DNA where mutation plus LDL-C in DFHDNA where mutation plus LDL-C in DFH + PFHCompared to LDL-C only, use of DNA where a mutation can be foundplus using LDL for identification of FH relatives in DFH + PFH gave most QALYs,with an Incremental Cost Effectiveness Ratio of ~£2700/QALYCompared to the NICE threshold of £20,000 this isVERY GOOD VALUE !
20 Funding now identified for 2009-2010 national roll out Audit of FH management in UKHumphries, Young, Potter et alOn-going through Royal College of PhysiciansObtained 1 yr funding from DHEstablished Steering group with reps from Colleges/stakeholdersDeveloped web-based information capture system using NICE recsTrialled in 14 lipid clinics throughout England and Wales – 248 notesReported in June 2008.Patient management goodAdditional resources will be needed to manage increased numbersFunding DNA testing not widely available (1/14)No systematic CT - opportunistic onlyOnly ad hoc shared care and pediatric arrangementsKey FindingsFunding 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 NetworkFH clinics run by LipidologistsAccess to Pediatric inputTrained “Genetic” FH Nurses for Cascade TestingDNA testing by accredited Genetics LabsNational Register – link families and avoid duplicationAppropriate Computer software and connectivityCore Data set and agreed Quality StandardsAudit of serviceXXXAgreed 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 LineDequker et al 2004, Medical Archaelogy IMAJyearsMadonna Lisa Maria di GherardiniBorn Florence 1479Died age 37 yearsXanthelasma?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 needsHadfield et al DH report 2007Key Requirements are:Draws PedigreeCollects agreed core (clinical and personal) data setMaintains high level of data confidentiality and security (encryption)Manages patient pathway (invite/follow up letters, appointments etc)Compatibility with healthcare IT structuresEnables connectivity across SHA/Devolved province borders.National Register is key NICE recommendationDutch StOh CT programme have developed a package that achieves this.Commercially available and supportedPackage being trialled in Wales -Ian McDowell et alWill report on findings in next 6 monthsWhy a National Register?
24 requires ability to contact Why is a National Register Needed ?Hadfield et al 2008Examined in DH FH projectOn ave 34% 10 rels lived outsidecatchment areaHighest % in London and SELowest contact successEfficiency of any CTrequires ability to contactdistant relatives.DNA testing by postalmouthwash sample
25 What about Screening children? Proposed by Wald et al BMJ 2007Screen 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 potentialof 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 modelCounter - Hadfield and Humphries BMJ 2007Currently only CT from known adult index cases is tried and tested and demonstrated to be acceptable and cost effective