Familial hypercholesterolaemia: a model of care for Australasia

Atherosclerosis Supplements 12 (2011) 221–263

Familial hypercholesterolaemia: A model of care for Australasia Gerald F. Watts a,∗ , David R Sullivan b , Nicola Poplawski c , Frank van Bockxmeer d , Ian Hamilton-Craig e , Peter M. Clifton f , Richard O’Brien g , Warrick Bishop h , Peter George i , Phillip J. Barter j , Timothy Bates a , John R. Burnett k , John Coakley l , Patricia Davidson m , Jon Emery n , Andrew Martin o , Waleed Farid p , Lucinda Freeman q , Elizabeth Geelhoed r , Amanda Juniper a,s , Alexa Kidd t , Karam Kostner u , Ines Krass v , Michael Livingston w , Suzy Maxwell s , Peter O’Leary s , Amal Owaimrin x , Trevor G. Redgrave a , Nicola Reid y , Lynda Southwell a , Graeme Suthers c , Andrew Tonkin z , Simon Towler aa , Ronald Trent q , Familial Hypercholesterolaemia Australasia Network Consensus Group (Australian Atherosclerosis Society)1 a

Lipid Disorders Clinic, Metabolic Research Centre and Department of Internal Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia b Department of Biochemistry and Lipid Clinic, Royal Prince Alfred Hospital, University of Sydney, New South Wales, Australia c South Australia Clinical Genetics Service, Genetics & Molecular Pathology Directorate, Women’s & Children’s Hospital, Adelaide, South Australia, Australia d Cardiovascular Genetics Laboratory, Royal Perth Hospital, University of Western Australia, Western Australia, Australia e Preventive Cardiology and Lipid Clinic, Gold Coast Hospital, Griffith University, Queensland, Australia f Baker IDI Heart and Diabetes Institute, Adelaide, South Australia, Australia g Department of Medicine, Diabetes and Endocrinology, Austin Hospital, University of Melbourne, Victoria, Australia h Department of Cardiology, Calvary Cardiac Centre, Calvary Health Care, Tasmania, Australia i Biochemistry and Pathology, Canterbury Health Laboratories, Lipid Clinic, Christchurch Hospital, University of Otago, Christchurch, New Zealand j Heart Research Institute, University of Sydney, Sydney, New South Wales, Australia k Core Clinical Pathology & Biochemistry, PathWest Laboratory Medicine WA, Lipid Disorders Clinic, Royal Perth Hospital, University of Western Australia, Western Australia, Australia l Department of Paediatrics and Clinical Biochemistry, The Children’s Hospital Westmead, Sydney, New South Wales, Australia m Cardiovascular and Chronic Care, Curtin University, and Nursing Research, St Vincent’s Hospital, Sydney, New South Wales, Australia n School of Primary, Aboriginal and Rural Health Care, University of Western Australia, Western Australia, Australia o Department of Paediatric and Adolescent Medicine, Princess Margaret Hospital, Perth, Western Australia, Australia p FH Family Support Group of Western Australia, Perth, Western Australia, Australia q Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital, University of Sydney, Australia r School of Population Health, University of Western Australia, Western Australia, Australia s Office of Population Health Genomics, Department of Health, Government of Western Australia, Australia t Clinical Genetics, Canterbury Health Laboratories, Christchurch Hospital, New Zealand u Cardiac Imaging Group, Department of Cardiology, Mater Hospital, University of Queensland, Australia v Department of Pharmacy Practice, Faculty of Pharmacy, University of Sydney, New South Wales, Australia w International Cholesterol Foundation, Sutton-Courtney, Oxfordshire, United Kingdom x Department of Dietetics, Familial Hypercholesterolaemia Clinical Support Service, Auburn Hospital, Sydney, New South Wales, Australia y Cardiovascular Prevention and Lipid Disorders Clinic, Christchurch Hospital, New Zealand z Cardiovascular Research Unit, Monash University, Melbourne, Victoria, Australia aa Health Networks, Department of Health, Government of Western Australia, Australia

∗ Corresponding author at: School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, GPO Box X2213, Perth, Western Australia 6847, Australia. Tel.: +61 8 9224 0245. E-mail address: [email protected] (G.F. Watts). 1 See Appendix 1.

1567-5688/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosissup.2011.06.001

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G.F. Watts et al. / Atherosclerosis Supplements 12 (2011) 221–263

Abstract Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated. To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described. This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Familial hypercholesterolaemia; model of care; adults; children; adolescents; diagnosis; genetic testing; cascade screening; assessment; treatment

Contents 1. 2. 3. 4. 5. 6. 7.

8.

9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Overview of algorithms for the model of care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection of index cases and diagnosis of FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assessment of adult patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis and assessment of children and adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. LDL-cholesterol and apoB targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Diet and lifestyle modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.1. Safety monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2. Medication adherence and tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Review intervals and shared care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Assessing atherosclerosis and CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. FH in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of children and adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. General and lifestyle considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. LDL-cholesterol targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Assessing atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5. Clinical monitoring and continuity of care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . LDL-apheresis and radical therapy for FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

223 225 227 227 228 230 232 232 232 232 234 234 234 234 235 235 235 236 237 237 237 238

Abbreviations: ABI, ankle brachial index; ACE, angiotensin converting enzyme; ALT, alanine aminotransferase; ApoA-I, apolipoprotein A-I; apoB, apolipoprotein B; ARMS, amplification refractory mutation system; AST, aspartate aminotransferase; BMI, body mass index; CACS, Coronary Artery Calcium Score; CCS, coronary calcium score; CHD, coronary heart disease; CIMT, carotid intima-medial thickness; CK, creatine kinase; CRP, C-reactive protein; CTCA, computerised tomography coronary angiography; CUS, carotid ultrasonography; CVD, cardiovascular disease; DLCNS, Dutch Lipid Clinic Network Score; EBESA, exon by exon sequence analysis; ECG, electrocardiography; EST, exercise stress test; FH, familial hypercholesterolaemia; FMD, flow-mediated dilatation; FDA, Food and Drug Administration; GP, general practitioner; HDL, high density lipoprotein; InterChol, International Cholesterol Foundation; LDL, low density lipoprotein; LFT, liver function test; Lp(a), lipoprotein(a); MBS, Medicare Benefits Schedule; MEDPED, Make Early Diagnosis to Prevent Early Deaths; MLPA, Multiplex Ligation Probe Amplification; MoC, model of care; NATA, National Association of Testing Authorities; NHMRC, National Health and Medical Research Council; NPAAC, National Pathology Accreditation Advisory Council; PBS, Pharmaceutical Benefits Scheme; PCSK9, proprotein convertase subtilisin/kexin type 9; PGD, pre-implantation genetic diagnosis; PND, prenatal diagnosis; RCPA, Royal College of Pathologists of Australasia; SHAPE, Screening for Heart Attack Prevention and Education Task Force; TGA, Therapeutic Goods Administration; TSH, thyroid-stimulating hormone.

10.

11. 12.

13.

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9.1. Indications, patient selection and targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. Methods for apheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3. Monitoring therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4. Cost considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5. Other therapeutic options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cascade screening: testing and risk notification of families . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. Risk notification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1.1. Contacting and informing families . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. Co-ordination of cascade screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. Risk notification without consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.4. Insurance cover and genetic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic testing of families . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory approach to genetic testing for FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2. A protocol for genetic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3. Assessing the significance of gene variants detected in index cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The web of care for FH: the optimal service model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.1. Focus, aims and objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2. Co-ordination and integration of care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inter-specialty links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3. Administrative and information technology support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.4. Clinical governance: audit, education, training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.5. Patient and family support groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.6. Into the future: chronic care model, commissioning, evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 1. FH Australasia Network Consensus Group and Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Writing committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steering committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Consensus process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 2. Dutch Lipid Clinic Network Criteria for FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 3. Simon Broome Criteria for FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 4. MEDPED Criteria for FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 5. Typical examination features of FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 6. Hypothetical Pedigree . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 7. ‘Real case’ Pedigree . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 8. Selected websites for clinical services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

238 238 238 240 240 240 240 240 242 242 242 243 243 243 245 245 245 247 247 248 249 249 249 250 250 250 250 250 250 251 251 251 251 251 252 252 253 254 254 255 255

1. Introduction Familial hypercholesterolaemia (FH) is the most common and serious form of inherited hyperlipidaemia [1]. FH is due to dominant mutations of genes predominantly affecting the function of the low-density lipoprotein (LDL) receptor that clears LDL particles from plasma [2,3], and hence results in marked elevation in plasma LDL-cholesterol concentration. FH is present from birth and accelerates the onset of all forms of atherosclerotic cardiovascular disease (CVD), especially coronary heart disease (CHD), by one to four decades [1,4,5]. Opportunistic diagnosis of FH followed by screening of family members, the so-called cascade screening, can detect individuals at an early stage of FH [4,6–11]. This is critically important because it enables early intervention including lifestyle measures, cholesterol-lowering medica-

tions (particularly statins), and management of other major cardiovascular risk factors [12–17b]. Alarmingly, less than 10% of cases with FH have been diagnosed in most Western communities, and only 5% are adequately treated [5,18–20]; Australia and New Zealand being no exception [21–23]. To address this demand in coronary prevention, the FH Australasia Network established a Consensus Group to devise a model of care (MoC) for FH from an Australian and New Zealand (Australasian) perspective. In the present context, the MoC was conceptualised as an overarching system, based on theoretical, experiential and evidence-based standards, for the provision of highest quality health care services for all patients with FH [24]. This MoC aims to establish a standard of care for FH patients in a framework within which future evidence and consensus may be included and developed, thereby extending

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Table 1 Grades for recommendations employed for consensus statements. Grade of recommendation

Description

A

Recommendation can be trusted to guide practice Recommendation can be trusted to guide practice in most situations Recommendations may be used to guide practice, but care should be taken in its application

B C

These grades were applied to each of the recommendations in Section 2. Individual members of the Steering Committee were asked to grade the recommendations based on their knowledge of the literature and what they considered best practice in caring for patients with FH. Gradings were discussed and after full consensus of the committee was reached a final grade was ascribed to each recommendation. All members of the FH Australasia Network Consensus Group approved the final gradings.

other proposed clinical care programs from Europe and North America [12,13,25–29]. The MoC is intended primarily for lipid disorder clinics in tertiary centres intending to initiate or develop a clinical service for FH. The MoC has been informed by published research, clinical experience, expert opinion and international guidelines for managing FH [5,12–16,30–34]. The major premises for these recommendations were published data on clinical efficacy and outcomes, but information on cost-effectiveness was also employed where available. Expert opinion was sourced from diverse stakeholders from

the disciplines of adult medicine, paediatric and adolescent medicine, clinical genetics, clinical biochemistry, nursing, pharmacy, general practice, population health, and health economics; a patient support group was also consulted. The MoC significantly extends and consolidates other Australian recommendations on the detection and management of FH [10,15,32,35–38]. The MoC is presented as a series of recommendations (Table 1, Section 2) and algorithms (Fig. 1) that if followed could provide a cost-effective, standardised system of care likely to have the highest impact on patient outcomes. The recommendations were graded according to a modified NHMRC classification [39], and reflected the full consensus of an expert committee that was based on knowledge of the relevant literature and best clinical practice. Algorithms were chosen to provide easy visualisation of the concepts underpinning the MoC. The algorithms are accompanied by background information and explanatory text and reflect the recommendations of the Consensus Group. This MoC should not be perceived as prescriptive, but as a tool for guidance. It should therefore be complemented by good clinical judgment and adjustments made to the model according to local requirements, protocols and resources. Acknowledging the lack of objective evidence supporting its clinical-efficacy and cost-effectiveness, this MoC for FH should be viewed as an evolving set of diagnostic and care pathways that will need periodic review, clinical appraisal and modification.

Diagnostic criteria Appendices 2, 3 & 4

Process Figure 2

Optimal components Figure 12 Adults Figure 2 & 3

Laboratory protocols Figures 10 & 11

Model of Care for FH

Clinical protocol Figure 9

Children/Adolescents Figure 4

Adults Figure 5

Children/Adolescents Figure 6 Process Figure 8

Fig. 1. Overview of algorithms for model of care for FH.

LDL-Apheresis Figure 7

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2. Summary of recommendations

Recommendation I

Models of care and components of service

Grade

Figs. 1 and 12

a. Models of care for familial hypercholesterolaemia (FH) should focus on detecting, diagnosing, assessing and managing index cases, as well as on risk notification and cascade screening of family members. b. Adults and children/adolescents will require different models of care. c. All services need to be integrated across several specialties and incorporated into primary care. d. Good clinical governance, teaching and training programs, and family support groups are integral to all models of care.

A

Recommendation II

Identifying index cases

Grade

Fig. 2

a. Index cases of FH should be sought amongst adults with premature cardiovascular disease in primary and secondary care settings. b. In adults a simple clinical tool based on the Dutch Lipid Clinic Network Score should be used. c. All patients with possible-to-definite FH should be referred to a lipid disorders clinic for more detailed assessment and institution of cascade screening.

A

A A A

A A

Recommendation III

Clinical assessment and management allocation of adults

Grade

Fig. 3

a. Secondary causes of hypercholesterolaemia should first be excluded. b. The diagnosis of FH should be made using both phenotypic and genetic testing. c. Patients should be stratified into risk categories according to presence of cardiovascular risk factors and personal history of cardiovascular disease. d. Risk stratification should guide the intensity of medical management.

A A A A

Recommendation IV

Clinical assessment and management allocation of children and adolescents

Grade

Fig. 4

a. Children (≥ 5 yr) and adolescents should be tested for FH after the diagnosis of FH has been made in a parent. b. Secondary causes of hypercholesterolaemia should first be excluded. c. With rare exceptions, children and adolescents should only be genetically tested for FH after a pathogenic variant (mutation) has been identified in a parent or first degree relative. d. Age- and gender-specific plasma LDL-cholesterol concentration thresholds should be used to make the phenotypic diagnosis of FH, an LDL-cholesterol ≥ 5.0 mmol/L indicating highly probable/ definite FH; two fasting lipid profiles are recommended. e. Patients should be stratified into risk categories according to age, presence of other cardiovascular risk factors, prematurity of family history of cardiovascular disease and the level of hypercholesterolaemia at diagnosis. f. Risk stratification should guide the intensity of medical management.

A

Recommendation V

Management of FH in adults

Grade

Fig. 5

a. All adult patients with FH must receive advice on lifestyle modifications and all non-lipid risk factors must be addressed. b. Plasma LDL-cholesterol targets for routine, enhanced and intensive management should be 3.3 mmol/L

LDL-C 5.0 mmol/L

Reassure patient and family and inform GP

Clinical assessment

Boys 10yr, Girls after menarche

1 or more of the following: Early (M 6.0 mmol/L

Lowest risk FH Expectant management

Intermediate risk FH Enhanced management

Highest risk FH Intensive management

Box 2: Information used for clinical assessment of children and adolescents with FH Mandatory: Age, gender, history including cardiovascular risk factors, psychological status, family history of hypercholesterolaemia and CVD, BMI, waist circumference, blood pressure, bruits, arcus cornealis, xanthelasma, tendon xanthomata, triglycerides, total cholesterol, LDL-C, HDL-C, Lp(a), apoB, smoking status, reproductive status, drug history Recommended/optional: glucose, insulin, CRP, creatinine, TSH, albuminuria, ApoA-I, CUS for early atherosclerosis, FMD of brachial artery for endothelial function.

Fig. 4. Diagnosis and assessment of children and adolescents. * See text for caveats.

preferably on genetic testing where a recognised mutation for FH has been detected in a parent [7,8,66]. Secondary causes of hypercholesterolaemia must be excluded [64a,b]. Irrespective of whether the diagnosis of FH will be made genetically, plasma LDL-cholesterol must be measured in all patients since the result is essential to guide therapy [96–98]. Predictive genetic testing of children for FH is also well justified as preventive treatment can be instituted before adulthood with lifestyle measures and pharmacotherapy [96–98,103,108] (see Fig. 6). Genetic counselling including discussion of the implications of DNA testing in children should be provided at the time the parent receives the genetic results confirming the diagnosis of FH [8,85,111–115]. Because of ethical issues involved in genetically testing minors [114,115], it is usual and best practice to first genetically test a phenotypically affected parent [64b]. This can also circumvent issues related to a non-paternity event. In rare circumstances, such as refusal of a parent to be tested first or when autosomal recessive FH is suspected [3], genetic testing may first be carried out in the child. Another special situation may arise when the child has significant hypercholesterolaemia without the detection of the family’s pathogenic mutation. In this case, after exclusion of secondary causes of hypercholesterolaemia and appropriate genetic counselling, other causative mutations for FH should be sought from the extended pedigree. Detecting an FH causing mutation would make the child or adolescent eligible for Pharmaceutical Benefits Scheme (PBS) government subsidy for a statin at

an LDL-cholesterol > 4.0 mmol/L when the family history of premature CVD or tendon xanthomata is unclear or unobtainable [116]. When an FH causing mutation is unknown in the parent, the diagnosis of FH in children should be based on age and sex adjusted LDL-cholesterol levels, the 95th percentile being 3.5 mmol/L for boys and 3.8 mmol/L for girls [37,48] (see Fig. 4). If employing the modified Simon Broome Criteria, the universal cut-off for probable FH is LDLcholesterol > 4.0 mmol/L [12,41]. At least two consecutive measurements of LDL-cholesterol over 6 months in fasting samples should be used to make the phenotypic diagnosis of FH [49,98]; a non-fasting lipid profile may be employed as an initial screening test, however. Knowledge of the child’s plasma LDL-cholesterol and whether a parent is being treated with a statin may provide a simple clinical tool for diagnosing FH [117]. Most children with plasma LDL-cholesterol >95th percentile for age and sex and an autosomal dominant pattern for inherited hypercholesterolaemia, in whom secondary causes of dyslipidaemia have been excluded, will have an FH causing mutation [118]. The thresholds for plasma LDLcholesterol concentration recommended above for making a phenotypic diagnosis of FH are compatible with those recently reported to accurately predict an FH causing mutation [46]. Whether using phenotypic or genetic approaches, screening children for FH requires expertise in working with and giving advice to families [8,84,98,119,120] and is best undertaken in close liaison with paediatric services and where indicated with genetic counsellors [115,121].

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All individuals with at least a possible diagnosis of FH should be clinically assessed according to mandatory and recommended (but optional) requirements shown in Fig. 4. With few exceptions, these are generally similar to those recommended previously for adults. Of the available non-invasive tests for subclinical atherosclerosis in children and adolescents, measurement of CIMT with ultrasonography is the most promising at present, but it requires special expertise and if used in risk stratification should be carried out according to recommended protocols [82,122]. With the exception of homozygous or compound heterozygous FH, boys aged less than 10 years and girls who have not reached the menarche should generally be considered to have low risk FH and receive expectant treatment. Boys over the age of 10 years and girls who have reached the menarche without cardiovascular risk factors or objective evidence of increased CIMT should be considered to have moderate risk FH and receive enhanced treatment. Boys over 10 years and girls who have reached the menarche, with a family history of very premature CVD, two or more major cardiovascular risk factors, or LDL-cholesterol > 6 mmol/L, should be considered to have high risk FH and receive intensive treatment [12,96–98]. Certain high risk children and adolescents with FH should ideally be managed in a joint adult-paediatric FH clinic [123]. Factors that may be used to triage patients for this clinic include family dynamics, current lifestyle of the family and child, adherence to treatment, severity of family history of CHD, and presence of other major cardiovascular risk factors (obesity, hypertension, diabetes and smoking) [123,124]. While all children with FH should ideally be referred to a paediatric service, we consider it feasible for affected parents and children to be reviewed together by an adult service in a ‘family clinic’ [123], provided staff have the required competencies and the environment of the clinic is appropriate. Young FH patients being reviewed in a paediatric clinic should be referred to an adult clinic around the age of 16 years, with appropriate arrangements made for transitional care and with close involvement of the GP.

7. Management of adults Fig. 5 shows the protocols for adult patients with FH allocated to standard, enhanced and intensive management. In parallel with lowering elevated plasma cholesterol, appropriate lifestyle modifications should be emphasised and all major non-lipid cardiovascular risk factors must be treated according to expert guidelines [14,16,17a,32,33,125–129]; offering advice and support on smoking cessation is mandatory. Low-dose aspirin should be used in highest risk FH and considered in intermediate risk FH [128].

(apoB) are given in Fig. 5. These targets have been chosen to be compatible with other therapeutic guidelines for the management of hypercholesterolaemia [13–16,32,59]; therapeutic targets should evidently be lower with increasing CVD risk. Measuring apoB may not, however, be necessary in leaner FH patients with plasma triglyceride concentrations 2.0 mmol/L [17a,58]. Even with contemporary treatments, achieving the absolute targets for LDL-cholesterol and apoB shown in Fig. 5 may not be attainable by some patients, particularly those with a higher baseline plasma cholesterol [61], in which case a more realistic general target of a 40–50% reduction from pre-treatment levels could be used [12,128]. 7.2. Diet and lifestyle modifications Diet and lifestyle modifications are cornerstones of the management of all types of dyslipidaemias [14–17a,32,33,59,130], including FH [13,131]. Diets should be low in saturated fat and energy and adjusted to achieve desirable body weight [15,132]. Dietary counselling by a registered dietician is recommended for all affected individuals and families [133]. Dietary supplementation with plant sterols or stanols should be considered [134]. Moderate intensity aerobic exercise for at least 30 min on 5 days of the week should be considered to prevent obesity and diabetes, with advice appropriately adjusted in those with established CHD [32]. Several strategies may be employed, where indicated and feasible, for improving long-term adherence to dietary and life-style changes, including involving the patient, setting goals, encouraging self-monitoring, frequent and prolonged contact, and motivational interviewing [135]. However, almost all patients will require medication to lower the elevation in LDL-cholesterol. Offering effective treatments and advice on smoking cessation is mandatory and appropriate management guidelines should be followed [32]. Alcohol consumption should be limited to no more than 2 standard drinks per day. Stress, anxiety and depression must be considered in all patients and managed accordingly [32,136]. 7.3. Pharmacotherapy

7.1. LDL-cholesterol and apoB targets The recommended therapeutic targets for absolute plasma concentrations of LDL-cholesterol and apolipoprotein B

In Australia, the PBS eligibility criteria for government subsidy for lipid modifying agents cover almost all adult patients with FH, particularly if the molecular diagnosis of

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Provide and reinforce information on: Healthy diet, tobacco avoidance, exercise, family and psychological support and medication adherence. Treat non-lipid risk factors: Diabetes, hypertension, obesity, smoking, consider aspirin

Adherence, tolerability + safety checks

Standard

Enhanced

Intensive

Review interval: 12 months

Review interval: 3-6 months

Review interval: as per clinical context

Diet + Plant Sterols + Statin ± Ezetimibe

Adherence, tolerability + safety checks

Consider interval noninvasive testing for coronary artery disease / atherosclerosis

Negative result

Positive result

Diet + Plant Sterols + Statin ± Ezetimibe ± Niacin

Adherence, tolerability + safety checks

Consider interval test of cardiac function: exercise ECG / Stress echocardiogram / myocardial perfusion scan

Consider interval noninvasive testing for coronary artery disease / atherosclerosis

Negative or stable result

Positive result or progression of disease

Diet + Plant Sterols + Statin ± Ezetimibe ± Niacin ± Resin ± Fenofibrate

Negative or stable result

Clinically significant positive result

Fig. 5. Management of Adults (see text for more information on action following initiation of therapy, treatment of special groups, shared care with GP and radical therapy).

FH has been confirmed with a DNA test [116]. In New Zealand government subsidies are similar, but the spectrum of drugs is slightly more restricted [137]. HMG CoA reductase inhibitors (or statins) are by far the most common and effective drugs to treat FH [104,107,128,129,138–146]. Statins decrease the incidence of CHD [143–145] and are estimated to be cost-effective in treating FH [147,148]. Reduction in the costs of statins will, however, make the medical care for FH even more cost-effective in the future. All the major statins are government subsidised in Australia, but only atorvastatin, simvastatin and pravastatin are subsidised in New Zealand. After initiation of statin therapy, all patients should be reviewed at 6–8 weeks to monitor LDL-cholesterol response, adherence, safety parameters and tolerability [61], and 6–12 monthly thereafter if targets are achieved and no problems documented. The statin should be up-titrated to the maximally recommended tolerable dose that achieves the therapeutic targets shown in Fig. 5; patients may require switching to more potent statins [61], such as atorvastatin or rosuvastatin. Higher risk patients who require greater lowering of plasma LDL-cholesterol and apoB will require other drugs, especially ezetimibe [149,150], but also niacin, fenofibrate and bile acid binding resins [151–154]. Patients with higher plasma LDL-cholesterol levels will require a combi-

nation of drugs to achieve therapeutic targets. Combination drug regimens that target LDL-cholesterol can decrease progression of CHD in patients with FH [155]. Niacin may be particularly indicated for lowering high plasma Lp(a) concentration [75,151,152]; in FH we recommend an Lp(a) < 0.5 g/L [75]. Fibrates would be relatively contraindicated with a history of untreated choleliathisis [156]. For patients not achieving treatment targets, additional agents should generally only be introduced after at least 12 months of testing and adjusting the statin regimen and confirming adherence to medication. In higher risk patients, additional agents should be considered after an earlier interval (e.g. 4–6 months) of testing the statin regimen. Residual hypertriglyceridaemia and low HDL-cholesterol (the so-called ‘atherogenic lipid profile’) while on a statin is an indication for considering treatment with niacin, a fibrate or higher doses of supplemental omega-3 fatty acid ethyl esters [152,157]. Hypertriglyceridaemia in FH patients should be managed according to recently published guidelines [158,159]. There is outcome evidence supporting use of lower doses of omega3 fatty acids in patients who have sustained a myocardial infarction [160]. Niacin, fibrates and omega-3 fatty acid ethyl esters, together with a very low fat diet, will also be indicated in rare instances of severe hypertriglyceridaemia

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to prevent acute pancreatitis [14,157,161]. There has been renewed interest from Japan in the therapeutic role of probucol [162], a drug formerly used to treat FH and withdrawn from the European and US markets because of safety concerns; use of the present formulation of this drug cannot be recommended. 7.3.1. Safety monitoring Plasma hepatic aminotransferases (ALT, AST), creatine kinase (CK) and creatinine levels should be measured routinely as baseline safety checks prior to starting medications [61,163]. Hepatic aminotransferases should be monitored according to the approved product information for the drugs, and checked at least every 3 months if there is a history of liver disease (e.g. chronic hepatitis or cirrhosis) or more frequently if plasma levels rise to three-fold greater than the upper reference limit; measurement of serum bilirubin may also be used to indicate the severity of liver toxicity. Plasma CK should be measured when musculoskeletal symptoms are reported. Particular vigilance is required in patients receiving higher doses of a statin, and patients predisposed to statin side-effects, specifically the elderly and those taking multiple medications including the combination of a statin with a fibrate [163,164]. Patients on niacin also require monitoring of plasma glucose and uric acid because of a small, but significantly increased risk of hyperglycaemia and hyperuricaemia [165]. Plasma ALT and AST should be measured about every 6 months in patients receiving statin–niacin and statin–fibrate combinations. Evidence of chronic kidney disease, as estimated by an elevation in plasma creatinine and fall in estimated glomerular filtration rate, would be a precautionary indication to initiate treatment with, or switch to, a statin that is not eliminated by the kidney [61]. Statins should not be initiated if the baseline plasma, ALT, AST or CK levels are >3 times the upper reference limit. Discontinuation of the statin or revision of the dose or regimen is required when the plasma aminotransferase or CK levels rise to >3 times the upper reference limit on treatment. Alternative agents such as a ezetimibe or bile acid sequestrants may need to be substituted for a statin. 7.3.2. Medication adherence and tolerance Pharmacists could play a key role by monitoring patients’ use of therapy, flagging non-adherent patients to GPs and clinics, reducing therapeutic complexity and by more direct involvement in improving adherence to medication [166–169]. FH patients who are non-adherent to therapy are best reviewed in a dedicated clinic that could involve input from pharmacy, clinical pharmacology, psychology and nursing [170]. Action plan interventions may be more effective in FH than interventions aimed at altering perceptions about taking statins [171]. Detailed communication and discussion of an individual’s family history of CVD may improve adherence to treatment [89,90]. Health literacy must also be considered [172,173]. The underlying causes of hypercholesterolaemia and adherence to statin therapy remains a

significant issue amongst many at risk patients who have not specifically been diagnosed with FH [174,175]. This also needs addressing at a primary care level in the community [176–178]. Poor control of hypercholesterolaemia and other risk factors for atherosclerosis is a particular on-going concern in all patients with CHD [179,180]. Patients who are intolerant of medications require special support and follow-up [170]. Musculoskeletal side-effects can be frequently reported with statins and require specialist care [170,181]. Potential drug interactions with statins should be closely monitored, [163] noting the increased risk with drugs that are metabolised by CYP3A4 with simvastatin and atorvastatin and by CYP2C9 with rosuvastatin and fluvastatin [61,163]. Ezetimibe is well tolerated and has a statin dose sparing effect [149,150]. Bile acid binding resins have frequent gastrointestinal side-effects (e.g. constipation and abdominal discomfort) and can affect the absorption of other drugs and fat soluble vitamins [153]; tolerability is greatest with colesevelam [182]. Resins should be taken with meals and gastrointestinal side-effects minimised by increasing fluid and fibre intake and use of stool softeners [153]. Flushing is a problem with niacin, but this is diminished with the newer formulations (Niacin-ER, Tredaptive) and with coadministration of aspirin [151,152]; hyperglycaemia can be a particular problem in FH patients with impaired glucose tolerance or diabetes, and hyperuricaemia in those with a history of gout [165]. Co-administration of fibrates and a statin can increase the risk of myopathy, but this is diminished significantly when a statin is combined with fenofibrate [156,163]. 7.4. Review intervals and shared care Uncomplicated patients on routine therapy may be referred back to the GP for long-term follow-up, but should also be reviewed annually in a lipid disorders clinic. Those receiving enhanced care should also be monitored in the lipid clinic at 3–6 monthly intervals until plasma LDL-cholesterol targets are achieved and if stable should be reviewed annually in this clinic with 6 monthly follow-up by the GP. Patients receiving intensive management should be retained in the lipid disorders clinic and reviewed at intervals determined by clinical context and requirements. When changing medication and increasing doses, patients may need more frequent review. Systems for the shared care of FH patients between specialties and primary care need to be further investigated in order to appropriately inform future MoCs for FH [68]. 7.5. Assessing atherosclerosis and CHD CTCA, CUS, ankle-brachial index measurement, stress echocardiography, treadmill ECG and myocardial nuclear perfusion scanning are all potential options for monitoring subclinical atherosclerosis and/or symptomatic coronary disease [76–78] (see Fig. 5). Consistent with expert recommendations [76–78,91], we consider that there is potential

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value in non-invasive testing in asymptomatic FH patients for atherosclerosis and coronary disease. However, non-invasive testing has been better validated for assessing target organ damage and stratifying risk than for monitoring progression of disease [13,79]. Nevertheless, clear evidence of progression of atherosclerosis in coronary, carotid or femoral arteries should be a clinical indication for intensifying treatment and attaining the recommended targets for LDL-cholesterol and apoB [13,77,183]. The intervals for repeat testing shown should be determined by clinical judgment and available resources. With CUS, the choice of equipment, technical aspects and operator training must be followed according to expert recommendations [78,82,122]; imaging protocols must be comprehensive and standardised, and age- and sexspecific reference values for CIMT and a detailed assessment of plaques should be employed. CUS is better suited for children and younger patients owing to absence of radiation risk, while CTCA may be useful to assess plaque burden and obstructive stenosis in asymptomatic adult patients. Future developments and refinements in cardiac CT imaging may allow this imaging modality to be fully incorporated into clinical algorithms for assessing atherosclerosis and CHD in FH. All asymptomatic patients should proceed to a functional test, ideally a stress echocardiogram. All ‘positive’ treadmill tests, myocardial perfusion scans and stress echocardiograms should be followed by referral to a cardiologist for the consideration of invasive coronary angiography and appropriate further care [13,78,110]. Patients with more than 70% stenosis of the internal carotid artery should be referred for consideration for revascularization [184,185].

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in offspring who inherit the condition [189,191]. Bile acid binding resins are the only safe agents to control hypercholesterolaemia in pregnancy, but only modestly lower plasma LDL-cholesterol levels and poor tolerability related to gastrointestinal side-effects remains a major problem [129,153]. A newer formulation, colesevelam, is more tolerable than the older resins [182]. Pregnant women with heterozygous FH and established CHD, or with homozygous FH, should be considered for LDL-apheresis [95,129]. During breast feeding, resins could be employed to lower LDL-cholesterol where indicated. More data are required on the outcomes of pregnancy in women with FH and on the effect of statins on the foetus in the first trimester; an appropriate registry of patients is recommended. Particular considerations are also required concerning future pregnancy when one or both members of a couple have FH. In these circumstances, there are a number of options available which enable the couple to avoid having a child affected by FH. These options include not conceiving, adoption (local and overseas), using donor gametes, prenatal diagnosis (PND) using chorionic villus sampling or amniocentesis and pre-implantation genetic diagnosis (PGD) [192,193]. There are a number of issues associated which each of these choices and couples may find it useful to meet with a counsellor who has expertise in reproductive counselling. Couples considering PND or PGD should be referred to a clinical genetics service for counselling and pre-test work up, ideally prior to conceiving.

8. Management of children and adolescents 7.6. FH in women Special considerations apply to the management of FH in women [43,186]. CHD risk is lower in women than men with FH [43,73,187]. Women may therefore be less likely to be treated with a statin at a younger age, but this needs revision according to a detailed family history of premature CVD, the presence of other cardiovascular risk factors and the rate of progression of CIMT [43,55–57,74,75,188]. Low estrogen-containing oral agents, intra-uterine devices and barrier methods are the preferred approaches to contraception in women with FH [186]. The latter two options should be particularly recommended to women older than 35 years who are of childbearing potential. Pre-pregnancy counselling is recommended for all women [66,129,186,187]. Statins and other systemically absorbed lipid regulating medications should be discontinued 3 months prior to planned conception and during pregnancy and lactation [186]. However, women who fall pregnant accidentally while taking a statin could be re-assured that the likelihood of any foetal complications is small [189,190]. The risks for future pregnancy and the foetus should be discussed at least annually with all women and girls of childbearing age. Controlling hypercholesterolaemia during pregnancy is particularly important in women with established CHD, and it may also decrease the severity of FH

Fig. 6 summarizes the management of FH in children and adolescents. 8.1. General and lifestyle considerations All patients, and ideally all immediate family members, should receive expert advice on lifestyle modifications including healthy eating, regular exercise and avoidance of cigarette smoking [12,97,103]. Prevention of obesity, metabolic syndrome and diabetes is paramount in FH [97]. Psychological counselling and social support may be required in special circumstances in certain families with FH [8,84,124]. Parents of affected children must not smoke. Non-cholesterol cardiovascular risk factors such as diabetes, hypertension and obesity should be treated according to relevant expert guidelines [97]. There is clear value in reviewing patients in a paediatric clinic, but we recommend that the paediatrician has some expertise in clinical lipidology and in the prevention of CVD [72]. A good, practical alternative is a family based clinic in which affected children, adolescents and their parents can be reviewed collectively by a multidisciplinary team [123]. Lowest risk FH should be treated with a fat modified diet and plant sterol supplementation [97,103,134,194],

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Provide and reinforce information on: Healthy diet, tobacco avoidance, exercise, family and psychological support and medication adherence. Treat non-lipid risk factors: Diabetes, hypertension, obesity, smoking

Expectant management

Enhanced management

Intensive management

Target LDL-C 5 mmol/L

Yes

Not Suitable Homozygous or compound heterozygous FH

239

Assess suitability for LDL-apheresis

Not Suitable Heterozygous FH

Consider enrolment in clinical trial of new treatments or applying via special access scheme for drugs in development for FH

Suitable

Liaise with transfusion service to select LDL-apheresis method, regimen and set efficacy and safety parameters

Homozygous or compound heterozygous FH

Apherese 1.5 – 2 plasma volumes for 2 – 4 hours every 2 – 3 weeks, continue statins and other drugs, avoid ACE inhibitors

Therapeutic target Time average LDL-C ABOB > PCSK9) [3,66] (Fig. 10). All results from commercial chip or kit technology that identify a gene variant as being present should be confirmed using the second validated testing method. This is a requirement of good laboratory practice [264,266] and relates to the potential analytical errors with the commercial methods. It should be noted that the protocol in Fig. 10 refers to diagnostic testing (mutation searching) for FH in a phenotypically defined ‘index case’. In a predictive testing setting the laboratory will already know the mutation in the index case and there is no need to screen for mutations other than directly testing for the one identified in the family [8,66].

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To increase acceptability, genetic testing for FH in children should be available using DNA extracted from either blood or buccal samples [263]. 12.3. Assessing the significance of gene variants detected in index cases Various pieces of evidence are used to determine the significance of an identified gene variant [264] and this clearly also applies to genetic testing for FH [66]. These include the published literature (including database entries), epidemiologic studies, in vitro and (preferably) in vivo demonstration that the variant causes a functional abnormality, and in silico (molecular software) assessment [284,285]. For practical reasons, in silico assessment coupled with search of the literature and established databases [267,286] are the usual primary sources used for assessing the significance of a gene variant. Unfortunately, published literature may in general contain errors, so careful assessment is required. In silico data are also variable in quality, particularly when it comes to assessing splicing mutations [287]. Patients and their managing clinicians should also be aware that a laboratory interprets each genetic test result in accordance with the best information available at the time of the test, and that it is possible that new information may emerge which results in a change in how a genetic test is interpreted. Particular care needs to be taken when classifying a gene variant as a pathogenic mutation, since it may be used in predictive genetic testing of asymptomatic individuals. If a variant of uncertain significance (either previously reported or novel) is detected, it is not appropriate to regard it as pathogenic. Clinical management of the individual and their family should be based on the plasma lipid phenotype (and other clinical criteria) and not on the genetic test result [12,13,26,38]. Fig. 11 provides a general approach for assessing and reporting the outcome of genetic testing for FH in a phenotypically defined index case. The significance of a gene variant should be assessed as recommended above. The formal laboratory report of the FH variant/mutation should detail the standardised methods used and the evidence supporting the classification [264]. If a pathogenic variant (mutation) is identified the report should also make the recommendation that further relatives be genetically screened for FH [264]. Where no gene variant or pathogenic mutation is detected, the report should include the caveat that such a result does not definitively exclude the diagnosis of FH.

13. The web of care for FH: the optimal service model Fig. 12 encapsulates the multiple components that should ideally comprise a comprehensive healthcare model for FH. The recommendations and MoC described in this document provide detailed pathways for the principal clinical compo-

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Dutch Lipid Clinic Score > 3 in Index Case Prioritise >8 definite, 6 – 8 probable, 3 – 5 possible

Consents to Genetic testing

Definite and Probable FH

Possible FH

Screen 1 Commercial method for detecting specific pathogenic variants

Screen 1 Commercial method for detecting specific pathogenic variants

Variant absent

Variant absent

Screen 2 MLPA ‡

Variant present Confirm by sequencing and / or appropriate alternative method if available

Variant absent

Issue report

Screen 3 Comprehensive exon by exon sequencing

Variant present Assess significance of gene variant (See Figure 11)

Screen 2 MLPA ‡

Variant absent

Issue report Include caveat that FH due to rare gene variants/mutations cannot be excluded Fig. 10. A laboratory protocol for genetic testing an ‘Index Case’ considered to have phenotypic FH. ‡ MLPA – Multiplex Ligation Probe Amplification.

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‘Index case’ consents to genetic test

Genetic testing as per Figure 10

Variant detected

No variant detected

Variant of uncertain significance Issue Report with caveat that FH cannot be excluded

Assess significance of variant * Benign variant Pathogenic variant (mutation)

Issue Report With appropriate recommendation for testing relatives (See Figure 8 & 9)

Fig. 11. Assessment and reporting of the outcome of genetic testing in an ‘Index Case’. *See text for further details.

nents shown in Fig. 12. This MoC represents an overarching system that significantly extends and updates other published service models [12,13,25–28].

health service provision for FH should be to identify most people with the condition in the community, aiming to achieve realistic targets in given time-frame, e.g. 30% detection rate after 3 years of service implementation.

13.1. Focus, aims and objectives 13.2. Co-ordination and integration of care Health service provision should focus on three main areas: patient care services, laboratory services, and research and clinical audit. The aims, objectives, expectations, outcomes and key performance indicators for each of these should be clearly identified and documented. Research and audit agendas for FH have been published elsewhere [12,37,288]. Care pathways for the seamless flow of patients between relevant specialties and other health providers, including primary care, should be specified and developed. The general aim of clinical care should be to identify, assess, manage and treat children and adults with FH to the highest level of clinical excellence. The primary therapeutic objective is not only to reduce cardiovascular risk related to elevation in plasma LDL-cholesterol [1,2,12,13], but also to treat other cardiovascular risk factors including obesity, hypertension, type 2 diabetes, metabolic syndrome and smoking [17a,32,33,43,55–57,74,125,127]; psychological and psychosocial factors must also be addressed [8,83–86,124,136,289]. A major long-term objective of

To achieve the clinical aims and objectives of the healthcare model for FH requires a dedicated multidisciplinary service [110] that is best co-ordinated by a lipid disorders clinic [26,71]. This service should be managed by suitably credentialled personnel operating out of departments of internal medicine, endocrinology or cardiology. Physicians who regularly manage patients with FH should have specialist training in clinical lipidology and competencies in the prevention of CVD [26,72], and be credentialled to supervise the training of junior physicians. Uncomplicated patients could be referred back to their GPs for long-term care but should be reviewed annually in a lipid disorders clinic. Existing clinics may need to up-skill their approaches to cascade screening for FH [9,290]. GPs should actively seek index cases in their practice by recognizing the importance of the family history of CVD and marked hypercholesterolaemia [68]. However, the optimal method for systematic identification of FH in primary care needs to be defined and a specific MoC devised

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Influencers & Stakeholders Department of Health Policy Makers Health Networks Atherosclerosis Association Family Support Group National Heart Foundation

Audit & Research Program Registry, Clinical & basic Science, Clinical trials, Epidemiology & Health Economics

Specialist & Primary Care Physicians, Physiciansin-training. Training, Credentialing, Professional development

Structured Clinical Management Program Shared between specialist clinics and primary care

Structured Education Program For community and health providers, multidisciplinary case conferences, journal clubs, accreditation

Specialised AdultPaediatric Service Family Clinics

Patient & Family Support Groups Consultation, Education, Advocacy

Administrative, Secretarial & Information Technology Services Support for Clinics, Outreach services and FH Registry

Cardiac & Imaging Facilities Stress testing Ultrasonography Echocardiography Cardiac CT Scanning

Clinical Liaison Cardiology Cardiac Rehabilitation Cardiothoracic Surgery Stroke unit Vascular Surgery

Specialist Nurses & Allied Health Support Pharmacy / Medication support Nutrition Psychology Exercise Lay counselling Training & Professional Development

Medical Laboratory Services Routine and Specialising in lipids and lipoproteins

Specialised Laboratory for Genetic Testing Service and research

Clinical Genetics, Family & Genetic Counselling Defined clinical pathways

Fig. 12. The web of care for FH: the optimal service model.

and tested. Decentralization of the management of FH should be a major objective of future developments. As FH services develop further in the community, the specific roles of general practice and other members of the primary care team will become clearer and inform future MoCs. Outreach lipid clinics in the community would be a useful first step, but clinical protocols need developing and testing. Telehealth may have a role in the management of FH in Australia, [291] but its cost-effectiveness remains to be evaluated. Patients aged 7.5 mmol/L OR LDL-C > 4.9 mmol/L AND Tendon xanthomata in the patient or in a first or second degree relative OR DNA based evidence of a LDL-receptor, familial defective apo B-100 or PCSK9 mutation Possible FH Raised cholesterol: In children ( 6.7 mmol/L OR LDL-C > 4.0 mmol/L In adults (> 16 years): total cholesterol > 7.5 mmol/L OR LDL-C > 4.9 mmol/L AND one of the following: Family history of premature myocardial infarction MI at 7.5 mmol/L In child (6.7 mmol/L

Appendix 4. MEDPED Criteria for FH MEDPED Criteria for the diagnosis of FH [42]. Age (years) Total and LDL-cholesterol (mmol/L) criteria for Diagnosing Probable Heterozygous Familial Hypercholesterolaemia (FH)

G (Asp227glu) in exon 4). TC = total plasma cholesterol (mmol/L), MI = Myocardial Infarction, CABG = Coronary Artery Bypass Grafting.

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Appendix 8. Selected websites for clinical services Selected websites that may be useful for clinical services caring for patients with FH. • International Cholesterol Foundation www.interchol.org New foundation, formed from the merger of MEDPED-International and HEART-EU, that has a strong focus on FH and provides useful links to international websites of interest to patients, researchers and health professionals. • HEART UK www.heartuk.org.uk Leading UK cholesterol charity that provides extensive resources for health professionals, patients and families on all aspects of the detection and management of FH. • Public Health Genomics Foundation, UK www.phgfoundation.org International foundation that publishes authoritative reports on the role of advances in genomics in health care, and has a particularly excellent document on services for inherited cardiovascular conditions. • National Heart Foundation, Australia www.heartfoundation.org.au Leading Australian charity that provides a wealth of resources for health professionals and the community on all aspects of primary and secondary prevention of cardiovascular disease. • British Heart Foundation www.bhf.org.uk Leading British foundation provides excellent resources for health professionals and patients, including informative videos on a wide spectrum of conditions and risk factors. • Centre for Genetics Education, New South Wales Health www.genetics.com.au Educational arm of NSW Genetic Service that provides genetic information of individuals and families affected by genetic conditions and health professionals who work with them. Activities include workshops and training programs. • Human Genetics Society of Australasia www.hgsa.org.au Premier Australasian society that provides educational materials, training, polices, guidelines and position statements on all aspects of human genetics. • Lipids Online, Baylor College of Medicine www.lipidsonline.org Established on-line facility, coordinated by Baylor College of Medicine (Houston, Texas, USA), providing resources (slides, visual meetings, commentaries), for clinicians, researches and educators on several aspects of dyslipidaemia, atherosclerosis and cardiovascular disease. • National Lipids Association (NLA), USA www.lipid.org US based multidisciplinary specialty society providing education, training, guidelines and position statements on all aspects of the detection and management of dyslipidaemia and related disorders. • Learn Your Lipids, NLA www.learnyourlipids.com Information for patients with dyslipidaemia, including FH, as provided by the foundation of the National lipid Association in the US. • New Zealand Guidelines Group www.nzgg.org.nz New Zealand group of experts that specialises in developing and implementing guidelines for best clinical practice; excellent resources on the assessment and management of all cardiovascular risk factors.

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• Rational Assessment of Drugs and Research (RADAR), National Prescribing Service (NPS) www.nps.org.au/health professionals/publications/nps radar Evidence based assessment of all new drugs, PBS listings and latest research for health professionals provided by the NPS, an independent organisation funded by the Australian Government Department of Health and Ageing. • Make Early Diagnosis Prevent Early Death (MEDPED) FH www.medped.org US based website of the original MEDPED Project coordinated by the University of Utah School of Medicine (Salt Lake City, UT, USA) focusing on all aspects of the management of FH, including education of patients and families and the first attempt at establishing a US registry. • Office of Population Genomics, FH Pilot Cascade Screening Program, Western Australia www.genomics.health.wa.gov.au/fh State funded office that aims to translate genomic knowledge into health benefits for WA health; resources provided relevant to the detection and management of FH • Wales FH Testing Service, Cardiff University www.fhwales.co.uk Leading FH service in the UK that provides useful information and resources for clinical practice, including activities of FH Family Forum. • FH Support Group of Western Australia www.fhfamilysupportgroup.websyte.com.au Website of the first support group in Australia for families with FH; provides relevant information, communication and support services. • FH Guideline Implementation Team Toolkit www.heartuk.org.uk/FHToolkit Invaluable resource for implementing the seminal NICE guideline 71 on identification and management of FH. • FH Australasia Network, Australian Atherosclerosis Society www.athero.org.au/FH Website of the FH Australasian Network, updated in 2011

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