Familial Hypercholeterolaemia Is it all about statins? Gerald F Watts DSc PhD MD FRACP FRCP Professor and Head, Cardiometabolic Service, Department of Cardiology, Royal Perth Hospital School of Medicine, University of Western Australia ACRA, 8 th August 2017
Elevated LDL cholesterol Atherosclerosis Liver with only 50% functional LDL receptors Myocardial infarction Coronary heart disease Mutations in LDL receptor, apolipoproteinb or PCSK9
At least 1 in 300 people have FH De Ferrante Circ 2016, Benn EHJ 2016, Wald NEJM 2016, Do Nature 2015, Futema Athero 2017, Abul-Husn Science 2016, Khera J Am Coll Cardiol 2016, Watts Int J Cardiol 2015, Shi Int J Cardiol 2014
Typical Features of FH Heterozygous FH Homozygous FH Cholesterol 7-14 mmol/l One major gene defect Arcus and tendon xanthomas possible CAD onset 35 yr Cholesterol 10-28 mmol/l Two major gene defects Tendon and cutaneous xanthomas before 10 yr CAD onset 15 yr
Cumulative LDL-Cholesterol LDL-Cholesterol Life-Years and CAD in FH 15 years 35 years 55 years CAD Ho FH +20yr Hz FH No FH + 20yr Threshold 0 0 3 6 9 12 15 28 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time Age (years) Nordestgaard B.G. et al. Eur Heart J 2013;34:3478-3490
Several Gaps in Care
Anatomy of Care for FH Screening and Detection of Cases Registries, Codifications, Research Agenda Patient Networks Advocacy Organization of Services Elements of Model of Care Diagnostic Tools Genetic Testing Assessment and Risk Stratification Targets and Treatments
Why Screen for FH? Serious consequences from youth Absent signs and symptoms in young Good tests Good therapy Cost-effective Responsibility
Screening:Where,Who,How? Coronary Care Primary Care Laboratory Medicine Cascade Screening Martin et al Curr Opin Lipidol 2017 April 19 th on-line
Diagnosis
Family history FH Criteria Score First-degree relative with known premature coronary and/or vascular disease (men aged <55 years, women aged <60 years) OR with known LDL-cholesterol above the 95 th percentile for age and gender First-degree relative with tendinous xanthomata and/or arcus cornealis OR Children aged <18 years with LDL-cholesterol above the 95 th percentile for age and gender Clinical history Patients with premature coronary artery disease (men aged <55 years, women aged <60 years) 2 Patients with premature cerebral or peripheral vascular disease (men aged <55 years, women aged <60 years) 1 Physical examination Tendinous xanthomata 6 Arcus cornealis before 45 years of age 4 1 2 FH Total score Definite >8 Probable 6-8 Possible 3-5 Unlikely <3 Blood Test LDL-cholesterol (mmol/l) LDL-C 8.5 8 LDL-C 6.5 8.4 5 LDL-C 5.0 6.4 3
Do you need to do genetic testing?
Value of Sequencing FH Genes in Patients with very High Cholesterol Khera et al J Am Coll Cardiol 2016; 67: 2578-90
Cascade screening is about families; you start with identifying the index case.
Family Cascade Screening Systematic search for affected individuals in the family of index case Relative 1st degree 50% Prevalence 2nd degree 25% 3rd degree 12.5% General Population 0.2 % or 1 in 500 Screening principle 1 FH patient >4 new FH
Predicting CVD Events in FH The SAFEHEART Registry Harrell s C-Index 0.85 Perez de Isla et al Circulation 2017; 135: 2133-44
Coronary Artery Calcium in FH Calcification in left anterior descending and left circumflex coronary arteries and in aorta
3 Principles for LDL lowering in FH Earlier Earlier Lower Lower Safer Safer
Treatment Options Heart healthy diet Established Drugs: Statin, Ezetimibe, Resin, Niacin New Drugs: PCSK9 mab, ApoB ASO, MTPI Radical Therapies: Lipoprotein Apheresis; Liver Transplant
Management of Adult FH Lifestyle modifications; address all risk factors At least 50% reduction in plasma LDL cholesterol and then target >> LDL cholesterol < 2.5 mmol/l (No CVD or other risk factors) LDL cholesterol < 1.8 mmol/l (CVD or other risk factors) Watts et al International Journal of Cardiology 2014
Attainment of target (%) Proportion of FH patients who reach LDL-C targets on therapy 100 80 60 40 20 0 1 2 3 4 5 6 7 8 9 10 Pijlman AH Atherosclerosis 2010;209:189-94 LDL-C target (mmol/l)
New LDL Lowering Therapies ApoB antisense MTP Inhibitors CETP inhibitors Thyromimetics PCSK-9 Inhibitors
Fully Human Monoclonal Antibody Production Monoclonal antibody gene Manufacturing cell Therapeutic monoclonal antibody Final product Patients
Lower LDL-C
PCSK9 mab SC injection Q2W
Adjusted Mean Change ± SE from Baseline (%) RUTHERFORD-2 Mean % change in LDL-C from baseline in Heterozygous FH Week 12 Weeks 10 and 12 20% 20% 10% 6% 10% 2% 0% 0% -10% % -10% % -20% -20% -30% -30% -40% -40% -50% -50% -60% -70% % 9%* %* % Placebo Q2W (N = 54) Placebo QM (N = 55) *P<0.0001 evolocumab treatment difference vs placebo Raal FJ, et al. Lancet 2014; doi.org/10.1016/s0140-6736(14)61399-4. -60% -70% %* % Evolocumab 140 mg Q2W (N = 110) Evolocumab 420 mg QM (N = 110) % %*
% patients Most hefh Patients Receiving Alirocumab on Background Statin Other LLT Achieved LDL-C Goals 90 80 70 FH I 72.2% Proportion of patients reaching LDL-C goal FH II 81.4% Alirocumab Placebo 60 28 50 40 30 20 10 0 11.3% 2.4% Very high-risk: <1.8 mmol/l High-risk: < 2.5 mmol/l. (<70 mg/dl) (<100 mg/dl)
Effect of PCSK9 mab on LDL-C while on Apheresis MM 38 yr, HoFH, CAD, Hypertension PCSK9 EVO mab 420 mg SC 4W
Anatomy of Care Screening and Detection of Cases Registries, Codifications, Research Agenda Patient Networks Advocacy Organization of Services Elements of Model of Care Diagnostic Tools Genetic Testing Assessment and Risk Stratification Targets and Treatments
Organization of Care Design model of care in context Multidisciplinary services, integrated with primary care: Cardiology Paediatric Genetics Imaging Transfusion Medicine Nursing Dietetics Psychology Pharmacy Pathology
Patient Support Groups and Networks Awareness raising Share/learn from each other Empower FH Patient Advocates Co-operate medical / science world Lobby for change
FH is the most potent hidden risk factor for premature CAD in families
7 Take Home Messages about FH 1) High cholesterol > 7 mmol/l 2) Premature CAD, LDL receptor defect 3) Prevalence at least 1:300 4) Dominant genetics: goes down the line 5) Screen and diagnose EARLY 6) Treat EARLY to LOW LDL-C target 7) PCSK9 inhibition gets to target
Who was this Person? Dequker et al Medical Archaelogy 2004 Madonna Lisa Maria di Gherardini Born Florence 1479 Died 1516 age 37 years Arcus Xanthoma Xanthelasma