SUPPLEMENTAL MATERIAL (Online data supplement)
for “Prevalence and management of familial hypercholesterolemia in patients with acute
coronary syndromes”
David Nanchen et al.
Methods Supplemental Material
Table S1 Dutch Lipid Clinic Network criteria for diagnosis of familial hypercholesterolemia
(FH) (n=4,778)
Table S2 Simon Broome Register criteria for diagnosis of familial hypercholesterolemia (FH)
(n=4,778)
Table S3 Baseline characteristics of patients with acute coronary syndrome (ACS), by use of
lipid lowering drugs before hospital admission (n=4,778)
Figure S1 Selection of study sample
Figure S2 Venn diagram for agreement between definitions of familial hypercholesterolemia
(n=4,778)
Figure S3 Prevalence of familial hypercholesterolemia (FH), by use of lipid lowering drugs
before hospital admission
a) patients not using lipid lowering drugs before hospitalization (n=3,353)
b) patients using lipid lowering drugs before hospitalization (n=1,425)
Figure S4 Sensitivity analyses for prevalence of familial hypercholesterolemia (FH) among
patients hospitalized for acute coronary syndrome (n=4,778)
1
Methods Supplemental material
Study population
The SPUM-ACS (Special Program University Medicine-Acute Coronary Syndromes) research
network included patients hospitalized from September 2009 to September 2014 for an ACS in 4
university medical centers in Switzerland (University hospital of Bern (BE), Geneva (GE),
Lausanne (LA) and Zürich (ZH)). Exclusion criteria comprised severe physical disability,
inability to participate or severe non-cardiac comorbidities leading to short life expectancy. ACS
was defined as the combination of symptoms of angina pectoris and at least one of the following
characteristics: ST-segment elevation or depression, T inversion or dynamic ECG changes,
evidence of positive troponin and known coronary heart disease (CHD). The final ACS diagnosis
was classified as STEMI (ST-segment elevation myocardial infarction), NSTEMI (non STsegment elevation myocardial infarction), or unstable angina.
LDL-cholesterol assessment
Total cholesterol, HDL-cholesterol and triglycerides were measured from the first blood draw at
the emergency department, within 24 hours of admission, and immediately processed locally
using standardized and certified dosage methods. LDL-cholesterol was calculated using the
Friedewald formula when triglyceride levels were below 4.5 mmol/l. LDL-cholesterol was
considered as missing for patients with triglyceride levels of 4.5 mmol/l or above. Because
patients with FH can have elevated triglyceride levels explained by genes and environmental
interactions, we did not exclude patients with high triglycerides levels (>= 2.3 mmol/l) from our
study sample.1 However, only patients with normal triglyceride levels (< 2.3 mmol/l) received
scoring for elevated LDL-cholesterol levels as recommended by the Dutch Lipid Clinic Network
2
score for FH diagnosis.2 For patients using lipid-lowering drugs before hospitalization for ACS,
we estimated untreated LDL-cholesterol levels based on type and dose of medication used before
hospitalization, applying a correcting factor for LDL-cholesterol adapted to the reported efficacy
of each drug, as previously done for similar analysis.3 One-year after hospitalization for ACS,
LDL-cholesterol levels were measured during the follow-up visit or extracted from laboratory
files of the physician in charge of the patient.
Use of lipid-lowering drugs
HMG-CoA reductase inhibitors (statins) that were taken prior to hospitalisation and prescribed at
discharge were systematically collected by trained study nurses. Type and dose of statins were
classified in three groups according to their intensity: (1) high-dose statins included atorvastatin
40-80mg or rosuvastatin 20-40mg; (2) moderate-dose statins included atorvastatin 10-20mg or
rosuvastatin 5-10 mg or simvastatin 20-40 mg or pravastatin 40-80 mg or fluvastatin 80 mg; and
(3) low-dose statins included simvastatin 10 mg or pravastatin 10-20mg or fluvastatin 20-40 mg.
Other lipid lowering agents than statins included fibrates, niacin, ezetimibe and bile acid resins.
For patients identified with FH, optimal statin management after discharge was defined as the
use of high-dose statins, 50% decrease in LDL-cholesterol levels, or a LDL-cholesterol equal or
below 1.8 mmol/l, as recommended by lipid guidelines.4
Covariables
Personal history of premature CHD was considered positive when men were younger than 55
years old and women younger than 60 years old at the time of ACS.5 Family history of premature
atherosclerosis was based on patient reports of a major cardiovascular event in a brother or father
3
younger than 55 years old, or a mother or sister younger than 60 years old. Education status was
dichotomized as having followed a high school or university graduation, or lower. Hypertension
was defined as a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or
use of blood pressure lowering drugs. Blood pressure lowering drugs included all medications in
the classes of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, betablockers, calcium-channel blockers, diuretics and nitrates. Smoking status was categorized into
current, former and never-smokers. Former smokers were those who smoked at least one
cigarette a day during at least one-year, and were non-smokers for more than one month before
inclusion. Diabetes, was either self-reported or diagnosed by the use of anti-diabetic medication,
or a hemoglobin A1c of 6.5% or greater at admission. Pre-existing cardiovascular disease was
defined as a previous diagnosis of CHD, ischemic cerebrovascular disease or periphery artery
disease. Attendance rate to cardiac rehabilitation was assessed from administrative data available
at discharge.
References
1. Hovingh GK, Davidson MH, Kastelein JJ, O'Connor AM. Diagnosis and treatment of familial
hypercholesterolaemia. Eur Heart J 2013;34:962-971.
2. Civeira F, International Panel on Management of Familial H. Guidelines for the diagnosis and
management of heterozygous familial hypercholesterolemia. Atherosclerosis 2004;173:55-68.
3. Besseling J, Kindt I, Hof M, Kastelein JJ, Hutten BA, Hovingh GK. Severe heterozygous
familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of
14,000 mutation carriers. Atherosclerosis 2014;233:219-223.
4
4. European Association for Cardiovascular P, Rehabilitation, Reiner Z, Catapano AL, De
Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ,
Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF,
Wood D. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the
management of dyslipidaemias of the European Society of Cardiology (ESC) and the
European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-1818.
5. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS,
Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer
KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL,
Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, TybjaergHansen A. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general
population: guidance for clinicians to prevent coronary heart disease: consensus statement of
the European Atherosclerosis Society. Eur Heart J 2013;34:3478-3490a.
5
Table S1
Dutch Lipid Clinic Network criteria for diagnosis of familial hypercholesterolemia (FH)
(n=4,778)
% subject
Variable
Grading
scoring
(number)
First degree relative with known premature atherosclerosis OR
with known LDL-cholesterol > 95th percentile, OR personal
history of premature (< 55 years men; < 60 years women)
36.8
1 point
(1,758)
cerebral or peripheral vascular disease, OR LDL-cholesterol 4.04.9 mmol/l*
Personal history of premature (< 55 years men; < 60 years
women) coronary heart disease OR first-degree relative with
tendon xanthomata and/or arcus cornealis OR first-degree relative
30.4
2 points
(1,451)
child below 18 years with LDL-cholesterol > 95th percentile OR
LDL-cholesterol 5.0-6.4 mmol/l*
3 points
Presence of arcus cornealis below 45 years
4 points
LDL-cholesterol 6.5-8.4 mmol/l*
5 points
Presence of tendon xanthomata
6 points
LDL-cholesterol > 8.5 mmol/l* OR functional mutation in LDL
receptor gene present
8 points
NA, not available
*
Only in those with triglyceride levels < 2.3 mmol/l
Possible FH: 3-5 points; probable FH: 6-7 points; definite FH >= 8 points
6
5.5
(265)
NA
1.0
(49)
NA
0.08
(4)
Table S2
Simon Broome Register criteria for diagnosis of familial hypercholesterolemia (FH) (n=4,778)
Total cholesterol > 7.5 mmol/l OR LDL-cholesterol >4.9 mmol/l
AND
% subject
Grading
scoring
(number)
First degree relative with known premature atherosclerosis (< 55
years men; < 60 years women)
Possible
FH
Personal history of premature (< 55 years men; < 60 years
women) coronary heart disease
Possible
FH
Definite
Tendon xanthomas
FH
Definite
DNA mutation
FH
NA, not available
7
2.7
(128)
4.2
(203)
NA
NA
Table S3
Baseline characteristics of patients with acute coronary syndrome (ACS), by use of lipid lowering
drugs before hospital admission (n=4,778)
Number
Demographics
Age, years
Female
Caucasian
Higher education1
Premature CHD2
Family history3
Smoking status
Never
Former
Current
Comorbidities
Hypertension4
Diabetes mellitus5
Pre-existing CVD6
Objective measures
Total cholesterol, mmol/L
LDL-cholesterol, mmol/L7
HDL-cholesterol, mmol/L
Triglycerides, mmol/L
Body mass index, kg/m2
eGFR, ml/min
Medication use at admission
Aspirin
Anti-hypertensives
Not using
lipid
lowering
drugs
3,353
Using of
lipid
lowering
drugs
1,425
p-value
61.7 (12.6)
727 (21.7)
3,155 (94.1)
871 (29.3)
1,191 (35.5)
806 (24.4)
66.6 (11.4)
281 (19.7)
1,340 (94.0)
293 (24.2)
260 (18.2)
407 (28.9)
<0.001
0.13
0.4
0.001
<0.001
0.001
<0.001
1,058 (31.9)
838 (25.2)
1,425 (42.9)
434 (30.9)
560 (39.8)
412 (29.3)
1,564 (46.7)
409 (12.2)
409 (12.2)
1,088 (76.4)
447 (31.4)
831 (58.3)
<0.001
<0.001
<0.001
5.2 (1.2)
3.4 (1.0)
1.2 (0.4)
1.4 (1.0)
26.9 (4.3)
90.5 (26.5)
4.3 (1.1)
2.5 (1.0)
1.2 (0.4)
1.5 (1.3)
27.6 (4.3)
84.9 (27.5)
<0.001
<0.001
<0.001
0.041
<0.001
<0.001
475 (14.2)
1,091 ( 32.5)
991 (69.6)
1,113 (78.1)
<0.001
<0.001
Data are given as number (percentage) or mean (standard deviation)
Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease; LDL, low-density
lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate
8
Defined as a high school or university graduation or higher
2
Age of onset for ACS before 55 years in males and before 60 in females
3
Based on major cardiovascular event in a brother or father younger than 55 years old, or a
mother or sister younger than 60 years old
4
Defined as a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or use
of blood pressure lowering drugs
5
Based on patients self-report, use of anti-diabetic medication/insulin or hemoglobin A1c of
≥6.5%
6
Defined as coronary heart disease, ischemic cerebrovascular disease or periphery artery disease
7
Including 65 missing values because of elevated triglycerides level of 4.5 mmol/l or above
9
Figure S1: Selection of study sample
10
Figure S2: Venn diagram for agreement between definitions of familial hypercholesterolemia (n=4,778)
11
Figure S3: Prevalence of familial hypercholesterolemia (FH), by use of lipid-lowering drugs before hospital admission
a) patients not using lipid-lowering drugs before hospitalization (n=3,353)
12
b) patients using lipid-lowering drugs before hospitalization (n=1,425)
13
Figure S4: Sensitivity analyses for prevalence of familial hypercholesterolemia (FH) among patients hospitalized for acute coronary
syndrome (n=4,778)
14