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Familial Hypercholesterolemia: Personalized public health epitomized
Joshua W. Knowles, MD, PhD Stanford and the FH Foundation
The known mechanisms causing familial hypercholesterolemia linked
to low-density lipoprotein (LDL) receptor (LDLR) function.
Samuel S. Gidding et al. Circulation. 2015;132:2167-2192
Copyright American Heart Association, Inc. All rights reserved.
PresenterPresentation NotesThe known mechanisms causing familial hypercholesterolemia linked to low-density lipoprotein (LDL) receptor (LDLR) function. Numbers 1 through 6 correspond to the mechanisms of LDLR dysfunction discussed in the text and Table 3. Familial defective apolipoprotein B (apoB) impairs the ability of the apoB to bind with the LDLR. LDLR adaptor protein (LDLRAP) impairs the ability of the LDLR to interact with LDL particles to extract cholesterol. Proprotein convertase subtulisin/kexin type 9 (PCSK9) gain-of-function (GOF) mutations inhibit LDLR function and increase the degradation of LDLRs.
FH is common and devastating Modern genetic studies support
Hopkins et al. J. Clinical Lipidology. 2011 Goldberg et al. J. Clinical Lipidology. 2011
a prevalence of ~1 in 250 50% of untreated men will have
MI by age 50 Causes 2-4% of heart attacks
before age 60 Cost $100s of millions
Lifelong exposure to high LDL causes early onset coronary disease.
Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273
The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
PresenterPresentation NotesLDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy. Data derived from Huijgen et al.20 and Starr et al.21 LDL, low-density lipoprotein; LDL-C, LDL cholesterol; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease; FH, familial hypercholesterolaemia.
The FH Foundation CASCADE FH Registry
CASCADE FH Registry Clinical Sites
CA (28)
G A (1 0)
NC (4)
NY (8)
UPenn Thomas Jefferson
Nemours
Stanford
Baylor
UT Southwestern
University of Kansas
Oregon Health & Science University
Vanderbilt
Preventive Cardiology Inc.
UCLA
Duke
NYU Rogosin
Massachusetts General Hospital
Johns Hopkins
Ohio State
Geisinger HS
U of Colorado
Atlantic HS
UCSF
Childrens Hospital Chicago
Central Maine Medical Center
Lancaster
Northwestern U
Hartford Hospital
University of Wisconsin
Mount Sinai Heart
Christiana Care HS
Boston Childrens
Minneapolis Heart Institute
Mayo
29 Approved to enroll
9 In progress
Cooks Children
Indiana Univ
West Virginia
University
Medical University of South Carolina
Childrens National HS
U of Rochester Medical Center
Treated LDL-C is suboptimal (HeFH) m
g/dL
250
200
150
235 229
143
180
Untreated LDL-C 100
Treated LDL-C 50
0 Adult Pediatric 18 Years
Female Male n=2095,
41% n=1424,
59% Average Age 57 52
Prior CAD 26% 37%
Prior MI 8% 16%
Prior PCI 13% 21%
Prior CABG 8% 17%
CAD more much more common in HeFH
5-6 fold higher than general population *
* DeGoma, E et al, Circ CV Genetics, 2016
FH disproportionately affects the risk of premature CAD
60%
50%
40%
30%
20%
10%
0%
CASCADE FH
* BRFSS
65 n=349 n=313 n=496 n=1,549 n=827
CAD MI PCI CABG
Data from Behavioral Risk Factor Surveilance System (BRFSS): MMWR, October 2011. Prevalence of coronary heart disease United States 2006-2010 https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6040a1.htm
https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6040a1.htm
Data from the CASCADE FH Registry Late Diagnosis and Treatment
GUIDELINES FOR SCREENING
Universal screening CASCADE FH Registry 9-11 yrs1,2 FH Screening Adult Screening Age 475 diagnosed with FH5
2 yrs1 21 yrs3
AGE 0 10 20 30 40 50
Treatment initiation4 Age 39 hyperlipidemia therapy initiated 8-10 yrs CASCADE FH Registry5
GUIDELINES FOR TREATMENT
1The AAP recommends screening for high cholesterol at age 2 if child has two parents with FH or high cholesterol; universal screening ages 9-11 2EAS Guidelines recommend universal screening for cholesterol ages 9-11 3ACC/AHA Adult Guidelines recommend universal screening of adults at age 21 4EAS Guidelines recommend US statin initiation for at ages 8-10 for FH 5CASCADE FH Registry participants are initiating lipid-lowering therapy at age 39 and receiving an appropriate diagnosis of FH at age 47
Estimating FH risk in the pooled cohorts
Individual pooled data from 6 large US epidemiologicalcohorts FHS, FHS Offspring, CARDIA, ARIC, CHS, NHANES III mortality
dataset 68,565 individuals with 1.2 million person-years of follow-up
20-79 year olds, categorized by baseline LDL level FH phenotype (LDL-C 190 mg/dL) found in 3850 (5.6%) non-FH, LDL
CHD events in the FH phenotype
Perak Circulation 2016
CV aging Men: 10-20 years Women: 20-30 years
15
PresenterPresentation NotesFigure 1. Unadjusted rates of coronary heart disease death or nonfatal myocardial infarction per 1000 person- years and underlying observed event numbers in (a) men and (B) women.Unadjusted event rates are graphed by index age and low-density lipoprotein cholesterol (LDL-C) category; LDL-C 190 mg/dL represents the familial hypercholesterolemia (FH) phenotype, and LDL-CRodriguez and Knowles, Circulation 2016 Perak et al., Circulation, 2016 Gupta et al. JACC, 2014
Dutch national program has been spectacularly successful
As of 2012: 5,151 index cases of genetically
positive FH identified
Resulted in screening of 60,000 family members
In total 27,069 FH cases identified 36% of the family members had a positive genetic test.
Costs for identifying 1 FH patient: 1200 euro Test almost 3 family members to identify 1 positive
FH mutation Costs effectiveness: costs per life year saved: 8700
Euro *
*Cost-Effectiveness Analysis of the Genetic Screening Program for Familial Hypercholesterolemia in the Netherlands David Wonderling, M.Sc., Marina A.W. Umans-Eckenhausen, M.D., Ph.D., Dalya Marks, Ph.D., Joep C. Defesche, Ph.D., John J.P. Kastelein, M.D., Ph.D., and Margaret Thorogood, Ph.D. Sem.Vasc.Med 2004:4:97
From: Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality
J Am Coll Cardiol. 2016;68(3):252-260. doi:10.1016/j.jacc.2016.04.054
FH patients who were statin users had a 44% RR reduction for the CAD and all-cause mortality versus those who had never used statins.
Translates to a number needed to treat (NNT) of 222 for 1 year of statin therapy to prevent a death in FH patients.
Far outstrips the NNT for 1 year for primary prevention in non-FH patients (NNT: 500)
indeed, it is lower than the NNT for secondary prevention in non-FH patients (NNT: 350)
Date of download: 11/3/2016 Copyright The American College of Cardiology. All rights reserved.
PresenterPresentation NotesStatins in FH: Consequences for CAD and All-Cause MortalityRetrieving data from patients identified by the Dutch screening program for familial hypercholesterolemia (FH), this retrospective cohort study sought to estimate therelative risk reduction for coronary artery disease (CAD) and mortality by statins in heterozygous FH patients. Moderate- to high-intensity statin therapy was associated with a relative risk reduction of approximately 44% for the primary prevention of CAD and all-cause mortality. *Derived from a Cox proportional hazard model analyzing statin use as a time-varying variable, while applying stabilized inverse-probability-of-treatment weighting (IPTW) and adjusting for age, other lipid-lowering therapy, antihypertensive medication, antidiabetic medication, and thrombocyte aggregation inhibitors (all-time varying). Variables included in the final model: statin use, age, lipid-lowering therapy, antidiabetic medication, antihypertensive medication, thrombocyte aggregation inhibitors (all-time varying) as wellas IPTW weights based on age at screening and start of follow-up, birth year, body mass index, low-density lipoprotein cholesterol (LDL-C), and triglycerides. CI=confidence interval.
Cascade testing for FH has a Tier 1 indication
Good evidence if FH is identified early and treated aggressively, morbidity and mortality reduced 80%
Highly cost effective We never find an individual
with FH, we only find families with FH
I FIGhT FH: Randomized Trial You have high cholesterol. It is important
that your relatives get checked.
You have this particular gene mutation that is causing your high cholesterol. It is important that your relatives get checked.
In the US, FH is rarely diagnosed
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Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273 The Author 2013. Published by Oxford University Press on behalf of the European Society of
Cardiology.
PresenterPresentation NotesEstimated per cent of individuals diagnosed with familial hypercholesterolaemia in different countries/territories, as a fraction of those theoretically predicted based on a frequenc