FH: Vision of the International Atherosclerosis Society. Raul D. Santos MD, PhD Sao Paulo, Brazil

Transcription

1 FH: Vision of the International Atherosclerosis Society Raul D. Santos MD, PhD Sao Paulo, Brazil 1

2 Declaration I have received honoraria related to consulting, talks or research from : Akcea, Amgen, Astra Zeneca, Biolab, Esperion, Kowa Merck, Pfizer, Novo-Nordisk, Sanofi/Regeneron 2

3 Mission: promote the scientific understanding of the etiology, prevention, and treatment of atherosclerosis. Federation of 64 societies Focus on developing regions Joint activities with member societies Practice documents Research and fellowship grants 3

4 Familial Hypercholesterolemia in a Nutshell Severe Dyslipidemia LDL-C usually > 190 mg/dl in adults (> 160 mg/dl in kids ) Prevalence 1/ heterozygotes 1/ homozygotes Elevated ASCVD risk (10-13X) Early ASCVD Cutaneous stigmata Family history Early CHD Dyslipidemia in the family Autosomal dominant inheritance Hard to normalize LDL-C Defesche JC et al. Nat Rev Dis Primers Dec 7;3: doi: /nrdp

5 FH Prevalence and its consequences 5

6 Estimated FH Prevalence Most FH Patients Are in Developing Countries!!! million people Watts G et al. J Atheroscler Thromb. 2016;23:

7 Country Spain Portugal Brazil Uruguay Mexico High prevalence of previous CVD in FH Index cases % With Molecular Diagnosis 8.3% 3.82% 0.27% 2.5% 0.13% % Index Cases CVD 13% 16.9% 23% 35% 38% Santos RD et al. J Clin Lipidol. 2017;11:

8 Benn et al. JCEM 2012, 97:

9 Bahia L et al. Arch Endocrinol Metab 2018 e pub 9

10 How FH is Diagnosed? 10

11 The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association Samuel S. Gidding, Mary Ann Champagne, Sarah D. de Ferranti, Joep Defesche, Matthew K. Ito, Joshua W. Knowles, Brian McCrindle, Frederick Raal, Daniel Rader, Raul D. Santos, Maria Lopes-Virella, Gerald F. Watts and Anthony S. Wierzbicki Circulation. published online October 28, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2015 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: Gidding S et al. Circulation 2015; 132: The online version of this article, along with updated information and services, is located on the

12 Gidding S et al. Circulation 2015; 132:

13 FH Mutation Presence and CAD Risk

14 For every 1,000 children 1-2 years of age = 8 FH subjects (4 children and 4 parents) LDL 99% Twice or LDL %95 + mutation Wald et al. N Engl J Med 2016;375:

15 Basic schematic procedure of clinical cascade screening Adapted with permission from Santos, R. D. Cascade screening in familial hypercholesterolemia: advancing forward. J. Atheroscler. Thromb. 22, (2015), Japan Atherosclerosis Society

16 Index Cases Hipercol Brasil Cascade Screening Program April 2018 Inconclusive n= 53; 3% No pathogenic variant; 70% Pathogenic variant n= 426; 27% 420 Families on Screening Heterozyotes 1719 Homozygotes 25 Compound Heterozygotes in trans 12 Compound Heterozygotes in cis 4 Double Heterozygotes 1 Total: 1610 Relatives No pathogenic variant n= 1398, 51% Courtesy Dr. Cinthia E. Jannes Pathogenic Variant n=, 1332, 49% Total:2730

17 Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial Author's Personal Copy hypercholest erolemia in Brazil P.R.S. Silva et al. / Atherosclerosis 263 (2017) 257e P~amela R.S. Silva a, *, Cinthia E. Jannes a, Theo G.M. Oliveira a, Marcio H. Miname b, Viviane Z. Rocha b, Ana Paula Chacra b, Maria Helane C. Gurgel c, Renan M. Montenegro c, Carlos Roberto M. Rodrigues Sobrinho c, Annie Seixas Bello Moreira d, Marcelo H.V. Assad d, Marina R.C. Pinto a, Mauricio Teruo Tada a, Raul D. Santos b, 1, Alexandre C. Pereira a, 1, Jose E. Krieger a,1 a Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of S~ao Paulo Medical School Hospital, S~ao Paulo, Brazil b Lipid Clinic, Heart Institute (InCor), University of S~ao Paulo Medical School Hospital, S~ao Paulo, Brazil c Cardiology Department, Walter Cantídio University Hospital, Federal University of Ceara, Fortaleza, Brazil d Cardiology Department, National Institute of Cardiology, Rio de Janeiro, Brazil a r t i c l e i n f o a b s t r a c t Article history: Received 12 April 2017 Received in revised form 30 May 2017 Accepted 21 June 2017 Available online 22 June 2017 Background and aims: There is controversy on the accuracy of different diagnostic criteria for familial hypercholester olemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. Methods: All index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age 18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. Results: Overall, 753 ICs were included and an FH causing mutation was found in 34%(n ¼ 257) of the Keywords: Familial hypercholesterolemia Low -density lipoprotein cholesterol Screening Index patient subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values 230 mg/dl (5.9 mmol/l) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were (95%CI: 0.704e 0.784) and (95%CI: 0.687e 0.774), respectively, p¼ Fig. 1. Proportion of genetic-positive cases based on our population prevalence Conclusions: rate (34.1%) In our usingpopulation, the three testedldl cutoff values 230 mg/dl for LDL-Cthat is a feasibl correspond e criterion to percentiles to25, indicate 50 and ICs to genetic testing. 75 for the studied population. Gray shaded individuals represent the percentage of confirmed positive cases while white shaded individuals represent the negative 2017 Published cases. by Elsevier Ireland Ltd. independently associated with mutation discovery, but they are becoming harder to find nowadaysdueto the use of lipid lowering therapy for hypercholesterolemia in the absence of an FH diagnosis Silva PRS Santos RD et al. Atherosclerosis 2017; 263: adequate for molecular FH screening in Brazilian individuals. However, using only LDL 230 mg/dl isenough to indicate an ICto genetic test, when obtaining some reliable information on all the

18 How to face the challenges? 18

19 Know Your Enemy! IAS Sponsored FH 10-Country Study EAS FH Study Collaboration Vallejo-Vaz A. et al. Atheroscler Suppl Dec;22:1-32 Watts G et al. J Atheroscler Thromb. 2016;23:

20 IAS Sponsored Pediatric FH Registry 20

21 Treatment of FH 21

22 Statins Reduce Mortality in FH 22

23 LDL-C Control in FH: SAFEHEART Study N= 2,752, mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximum LLT Perez de Isla et al J Am Coll Cardiol. 2016;67:

24 Heterozygous FH New Horizons: PCSK9 Inhibitors LDL-C values < 1.8 mmol/l (70 mg/dl) in refractory FH patients Rutherford % treated with evolocumab Odyssey FH I and II % in those receiving alirocumab 1-Raal et al. Lancet 2015; 385: Kastelein et al. Eur Heart J 2015; 36:

25 Ridker PM et al J Clin Lipidol 2018 e pub 25

26 Santos RD et al Lancet Diab Endocrinol 2016;4:

27 Severe Familial Hypercholesterolemia: Treating the Continuum At presentation (untreated LDL-C) LDL C >10 mmol/l (400 mg/dl) LDL-C >8.0 mmol/l (310 mg/dl) + one high risk condition LDL-C > 5 mmol/l (190 mg/dl) + two high risk conditions Realistic goal: reduce 50% LDL-C Ideal goal: LDL-C < 2.5 mmol/l (100 mg/dl) With subclinical atherosclerosis assessment Advanced subclinical atherosclerosis Coronary: A-Coronary artery calcium (CAC) score > 100 Agatston units, or > 75 th percentile for age and gender* Realistic goal: reduce 50% Ideal goal : LDL-C < 1.8 mmol/l (70 mg/dl) B-Computed tomography angiography (CTA) with obstructions > 50% or presence of nonobstructive plaques > one vessel. Presence of clinical atherosclerotic cardiovascular disease Realistic goal: reduce LDL- C 50% Ideal goal: LDL-C < 1.8 mmol/l (70 mg/dl) Santos RD et al Lancet Diab Endocrinol 2016;4:

28 Algorithm for Treatment of Severe FH Santos RD et al Lancet Diab Endocrinol 2016;4:

29 Murphy et al. GLOBAL HEART, VOL. 12, NO. 3, 2017 September 2017:

30 Challenges to developing countries! 30

31 31 Murphy et al. GLOBAL HEART, VOL. 12, NO. 3, 2017 September 2017:

32 IAS View on FH 32

33 Unmet need for FH: IAS View Frequent disease that needs to be recognized Early diagnosis = early statin treatment= potential for prevention Universal cholesterol screening and need for family cascade screening Implementation of molecular diagnosis in a more effective way Need for education lay people, physicians, authorities Need for newer therapies e.g. PCSK9 inhibitors for higher risk patients =risk stratification 33

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