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Circulation
CHOLESTEROL CLINICAL PRACTICE GUIDELINES
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/
AGS/APhA/ASPC/NLA/PCNA Guideline on the
Management of Blood Cholesterol
A Report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines
WRITING COMMITTEE MEMBERS
Scott M. Grundy, MD, PhD, FAHA, Chair*
Neil J. Stone, MD, FACC, FAHA, Vice Chair*
Alison L. Bailey, MD, FACC, FAACVPR
Craig Beam, CRE*
Kim K. Birtcher, MS, PharmD, AACC, FNLA
Roger S. Blumenthal, MD, FACC, FAHA, FNLA
Lynne T. Braun, PhD, CNP, FAHA, FPCNA, FNLA
Sarah de Ferranti, MD, MPH*
Joseph Faiella-Tommasino, PhD, PA-C
Daniel E. Forman, MD, FAHA**
Ronald Goldberg, MD
Paul A. Heidenreich, MD, MS, FACC, FAHA
Mark A. Hlatky, MD, FACC, FAHA*
Daniel W. Jones, MD, FAHA
Donald Lloyd-Jones, MD, SCM, FACC, FAHA*
Nuria Lopez-Pajares, MD, MPH
Chiadi E. Ndumele, MD, PhD, FAHA*
Carl E. Orringer, MD, FACC, FNLA
Carmen A. Peralta, MD, MAS*
Joseph J. Saseen, PharmD, FNLA, FAHA
Sidney C. Smith Jr, MD, MACC, FAHA*
Laurence Sperling, MD, FACC, FAHA, FASPC***
Salim S. Virani, MD, PhD, FACC, FAHA*
Joseph Yeboah, MD, MS, FACC, FAHA
*ACC/AHA Representative. AACVPR Representative. ACC/AHA Task Force on Clinical Practice Guidelines Liaison.
Prevention Subcommittee Liaison. PCNA Representative. AAPA Representative. **AGS Representative. ADA
Representative. PM Representative. ACPM Representative. NLA Representative. APhA Representative.
***ASPC Representative. ABC Representative.
The American Heart Association requests that this document be cited as follows: Grundy SM, Stone NJ, Bailey
AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,
Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA,
Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/
APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082-
e1143. DOI: 10.1161/CIR.0000000000000625.
ACC/AHA Task Force Members,
see page e1123
Key Words: AHA Scientifc Statements
 Guidelines  biomarkers, coronary
artery calcium score  pharmacological
 cardiovascular disease  cholesterol,
LDL-cholesterol  diabetes mellitus 
drug therapy  hydroxymethylglutaryl-
CoA reductase inhibitors/statins 
hypercholesterolemia  lipids  patient
compliance  primary prevention  risk
assessment  risk reduction discussion
 risk treatment discussion, secondary
prevention  ezetimibe  proprotein
convertase subtilisin/kexin type 9
inhibitor (PCSK9) inhibitors
(c) 2018 by the American Heart
Association, Inc., and the American
College of Cardiology Foundation.
https://www.ahajournals.org/journal/circ
e1082 June 18/25, 2019
Circulation. 2019;139:e1082-e1143. DOI: 10.1161/CIR.0000000000000625

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Grundy et al
2018 Cholesterol Clinical Practice Guidelines
Circulation. 2019;139:e1082-e1143. DOI: 10.1161/CIR.0000000000000625
June 18/25, 2019
CLINICAL STATEMENTS
AND GUIDELINES

TABLE OF CONTENTS
Top 10 Take-Home Messages to Reduce Risk of
Atherosclerotic Cardiovascular Disease Through
Cholesterol Management . . . . . . . . . . . . . . . . . . .  e1083
Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  e1084
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e1085
1.1. Methodology and Evidence Review . . . . . . . .  e1085
1.2. Organization of the Writing Committee. . . . .  e1086
1.3. Document Review and Approval . . . . . . . . . .  e1086
1.4. Scope of the Guideline . . . . . . . . . . . . . . . . .  e1086
1.5. Class of Recommendation and Level
of Evidence . . . . . . . . . . . . . . . . . . . . . . . . . .  e1087
1.6. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . .  e1087
2. High Blood Cholesterol and ASCVD. . . . . . . . . . . .  e1087
2.1. Serum Cholesterol, Lipoproteins, and ASCVD . .  e1087
2.1.1. Cholesterol, Lipoproteins, and
Apolipoprotein B. . . . . . . . . . . . . . . . .  e1087
2.1.2. Cholesterol, LDL-C, and ASCVD . . . . .  e1087
2.1.3. LDL-C and Other Risk Factors . . . . . . .  e1087
2.2. Measurements of LDL-C and Non-HDL-C . . .  e1088
2.3. Measurements of Apolipoprotein B
and Lipoprotein (a) . . . . . . . . . . . . . . . . . . . .  e1089
2.4. Monitoring Response of LDL-C to Statin
Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . .  e1090
3. Therapeutic Modalities . . . . . . . . . . . . . . . . . . . . . e1090
3.1. Lifestyle Therapies . . . . . . . . . . . . . . . . . . . . .  e1090
3.1.1. Diet Composition, Weight Control,
and Physical Activity . . . . . . . . . . . . . .  e1090
3.1.2. Lifestyle Therapies and Metabolic
Syndrome . . . . . . . . . . . . . . . . . . . . . .  e1090
3.2. Lipid-Lowering Drugs. . . . . . . . . . . . . . . . . . .  e1090
3.2.1. Statin Therapy. . . . . . . . . . . . . . . . . . .  e1090
3.2.2. Nonstatin Therapies . . . . . . . . . . . . . . e1091
3.2.3. Nonstatin Add-on Drugs to Statin
Therapy. . . . . . . . . . . . . . . . . . . . . . . .  e1091
4. Patient Management Groups. . . . . . . . . . . . . . . . .  e1091
4.1. Secondary ASCVD Prevention . . . . . . . . . . . .  e1091
4.2. Severe Hypercholesterolemia (LDL-C
>=190 mg/dL [>=4.9 mmol/L]) . . . . . . . . . . . . . .  e1095
4.3. Diabetes Mellitus in Adults . . . . . . . . . . . . . .  e1097
4.4. Primary Prevention. . . . . . . . . . . . . . . . . . . . .  e1099
4.4.1. Evaluation and Risk Assessment . . . . .  e1099
4.4.2. Primary Prevention Adults 40 to
75 Years of Age With LDL-C Levels
70 to 189 mg/dL (1.7 to 4.8 mmol/L). . .  e1102
4.4.3. Monitoring in Response to
LDL-C-Lowering Therapy . . . . . . . . . .  e1106
4.4.4. Primary Prevention in Other Age
Groups . . . . . . . . . . . . . . . . . . . . . . . .  e1107
4.5. Other Populations at Risk. . . . . . . . . . . . . . . .  e1111
4.5.1. Ethnicity . . . . . . . . . . . . . . . . . . . . . . .  e1111
4.5.2. Hypertriglyceridemia . . . . . . . . . . . . . .  e1112
5. Statin Safety and Statin-Associated Side Effects . . .  e1117
6. Implementation. . . . . . . . . . . . . . . . . . . . . . . . . . .  e1120
7. Cost and Value Considerations . . . . . . . . . . . . . . .  e1121
7.1. Economic Value Considerations:
PCSK9 Inhibitors . . . . . . . . . . . . . . . . . . . . . .  e1121
8. Limitations and Knowledge Gaps. . . . . . . . . . . . . .  e1122
8.1. Randomized Controlled Trials. . . . . . . . . . . . .  e1122
8.2. Risk Assessment . . . . . . . . . . . . . . . . . . . . . .  e1122
8.2.1. Continuing Refnement of PCE . . . . . .  e1123
8.2.2. Improvement in Lifetime Risk Estimate . .  e1123
8.2.3. Refnement of Clinician-Patient Risk
Discussion. . . . . . . . . . . . . . . . . . . . . .  e1123
8.2.4. Monitoring and Adjustment
of Treatment . . . . . . . . . . . . . . . . . . . .  e1123
8.2.5. Prognostic Signifcance of CAC . . . . . .  e1123
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  e1124
Appendix 1: Author Relationships With Industry
and Other Entities (Relevant)-2018
AHA/ACC/AACVPR/AAPA/ABC/ACPM/
ADA/AGS/APhA/ASPC/NLA/PCNA Guideline
on the Management of Blood Cholesterol
(August 2018) . . . . . . . . . . . . . . . . . . . . e1139
Appendix 2: Reviewer Relationships With Industry
and Other Entities (Comprehensive)-2018
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/
AGS/APhA/ASPC/NLA/PCNA Guideline
on the Management of Blood Cholesterol
(August 2018) . . . . . . . . . . . . . . . . . . . . e1141
TOP 10 TAKE-HOME MESSAGES TO
REDUCE RISK OF ATHEROSCLEROTIC
CARDIOVASCULAR DISEASE
THROUGH CHOLESTEROL
MANAGEMENT
1. In all individuals, emphasize a heart-healthy
lifestyle across the life course. A healthy
lifestyle reduces atherosclerotic cardiovascular
disease (ASCVD) risk at all ages. In younger indi
viduals, healthy lifestyle can reduce development
of risk factors and is the foundation of ASCVD
risk reduction. In young adults 20 to 39 years of
age, an assessment of lifetime risk facilitates the
clinician-patient risk discussion (see No. 6) and
emphasizes intensive lifestyle efforts. In all age
groups, lifestyle therapy is the primary interven
tion for metabolic syndrome.
2. In patients with clinical ASCVD, reduce low-
density lipoprotein cholesterol (LDL-C) with
high-intensity statin therapy or maximally
tolerated statin therapy. The more LDL-C is
reduced on statin therapy, the greater will be sub
sequent risk reduction. Use a maximally tolerated
statin to lower LDL-C levels by >=50%.
3. In very high-risk ASCVD, use a LDL-C thresh
old of 70 mg/dL (1.8 mmol/L) to consider
addition of nonstatins to statin therapy. Very
high-risk includes a history of multiple major
ASCVD events or 1 major ASCVD event and
multiple high-risk conditions. In very high-risk
ASCVD patients, it is reasonable to add ezetimibe
to maximally tolerated statin therapy when the
LDL-C level remains >=70 mg/dL (>=1.8 mmol/L).
In patients at very high risk whose LDL-C level
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remains >=70 mg/dL (>=1.8 mmol/L) on maximally
tolerated statin and ezetimibe therapy, adding a
PCSK9 inhibitor is reasonable, although the long
term safety (>3 years) is uncertain and cost effec
tiveness is low at mid-2018 list prices.
4. In patients with severe primary hyper
cholesterolemia (LDL-C level >=190 mg/dL
[>=4.9 mmol/L]), without calculating 10-year
ASCVD risk, begin high-intensity statin ther
apy. If the LDL-C level remains >=100 mg/dL (>=2.6
mmol/L), adding ezetimibe is reasonable. If the
LDL-C level on statin plus ezetimibe remains >=100
mg/dL (>=2.6 mmol/L) and the patient has multiple
factors that increase subsequent risk of ASCVD
events, a PCSK9 inhibitor may be considered,
although the long-term safety (>3 years) is uncer
tain and economic value is uncertain at mid-2018
list prices.
5. In patients 40 to 75 years of age with dia
betes mellitus and LDL-C >=70 mg/dL (>=1.8
mmol/L), start moderate-intensity statin
therapy without calculating 10-year ASCVD
risk. In patients with diabetes mellitus at higher
risk, especially those with multiple risk factors or
those 50 to 75 years of age, it is reasonable to use
a high-intensity statin to reduce the LDL-C level
by >=50%.
6. In adults 40 to 75 years of age evaluated for
primary ASCVD prevention, have a clinician-
patient risk discussion before starting statin
therapy. Risk discussion should include a review
of major risk factors (eg, cigarette smoking, ele
vated blood pressure, LDL-C, hemoglobin A1C [if
indicated], and calculated 10-year risk of ASCVD);
the presence of risk-enhancing factors (see No.
8); the potential benefts of lifestyle and statin
therapies; the potential for adverse effects and
drug-drug interactions; consideration of costs of
statin therapy; and patient preferences and values
in shared decision-making.
7. In adults 40 to 75 years of age without dia
betes mellitus and with LDL-C levels >=70 mg/
dL (>=1.8 mmol/L), at a 10-year ASCVD risk of
>=7.5%, start a moderate-intensity statin if a
discussion of treatment options favors statin
therapy. Risk-enhancing factors favor statin ther
apy (see No. 8). If risk status is uncertain, consider
using coronary artery calcium (CAC) to improve
specifcity (see No. 9). If statins are indicated,
reduce LDL-C levels by >=30%, and if 10-year risk
is >=20%, reduce LDL-C levels by >=50%.
8. In adults 40 to 75 years of age without dia
betes mellitus and 10-year risk of 7.5% to
19.9% (intermediate risk), risk-enhancing
factors favor initiation of statin therapy (see
No. 7). Risk-enhancing factors include family
history of premature ASCVD; persistently ele
vated LDL-C levels >=160 mg/dL (>=4.1 mmol/L);
metabolic syndrome; chronic kidney disease; his
tory of preeclampsia or premature menopause
(age <40 years); chronic infammatory disorders
(eg, rheumatoid arthritis, psoriasis, or chronic
HIV); high-risk ethnic groups (eg, South Asian);
persistent elevations of triglycerides >=175 mg/dL
(>=1.97 mmol/L); and, if measured in selected indi
viduals, apolipoprotein B >=130 mg/dL, high-sensi
tivity C-reactive protein >=2.0 mg/L, ankle-brachial
index <0.9 and lipoprotein (a) >=50 mg/dL or 125
nmol/L, especially at higher values of lipoprotein
(a). Risk-enhancing factors may favor statin ther
apy in patients at 10-year risk of 5-7.5% (border
line risk).
9. In adults 40 to 75 years of age without diabe
tes mellitus and with LDL-C levels >=70 mg/dL
to 189 mg/dL (>=1.8-4.9 mmol/L), at a 10-year
ASCVD risk of >=7.5% to 19.9%, if a decision
about statin therapy is uncertain, consider
measuring CAC. If CAC is zero, treatment with
statin therapy may be withheld or delayed, except
in cigarette smokers, those with diabetes mellitus,
and those with a strong family history of prema
ture ASCVD. A CAC score of 1 to 99 favors statin
therapy, especially in those >=55 years of age. For
any patient, if the CAC score is >=100 Agatston
units or >=75th percentile, statin therapy is indi
cated unless otherwise deferred by the outcome
of clinician-patient risk discussion.
10. Assess adherence and percentage response
to LDL-C-lowering medications and lifestyle
changes with repeat lipid measurement 4
to 12 weeks after statin initiation or dose
adjustment, repeated every 3 to 12 months
as needed. Defne responses to lifestyle and
statin therapy by percentage reductions in LDL-C
levels compared with baseline. In ASCVD patients
at very high-risk, triggers for adding nonstatin
drug therapy are defned by threshold LDL-C lev
els >=70 mg/dL (>=1.8 mmol/L) on maximal statin
therapy (see No. 3).
PREAMBLE
Since 1980, the American College of Cardiology (ACC)
and American Heart Association (AHA) have translated
scientifc evidence into clinical practice guidelines with
recommendations to improve cardiovascular health.
These guidelines, which are based on systematic meth
ods to evaluate and classify evidence, provide a founda
tion for the delivery of quality cardiovascular care. The
ACC and AHA sponsor the development and publica
tion of clinical practice guidelines without commercial

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CLINICAL STATEMENTS
AND GUIDELINES

support, and members volunteer their time to the writ
ing and review efforts.
Clinical practice guidelines provide recommenda
tions applicable to patients with or at risk of developing
cardiovascular disease (CVD). The focus is on medical
practice in the United States, but these guidelines are
relevant to patients throughout the world. Although
guidelines may be used to inform regulatory or payer
decisions, the intent is to improve quality of care and
align with patients' interests. Guidelines are intended
to defne practices meeting the needs of patients in
most, but not all, circumstances, and should not re
place clinical judgment.
Recommendations for guideline-directed manage
ment and therapy, which encompasses clinical evalu
ation, diagnostic testing, and both pharmacological
and procedural treatments, are effective only when fol
lowed by both practitioners and patients. Adherence to
recommendations can be enhanced by shared decision-
making between clinicians and patients, with patient
engagement in selecting interventions on the basis of
individual values, preferences, and associated condi
tions and comorbidities.
The ACC/AHA Task Force on Clinical Practice
Guidelines strives to ensure that the guideline writ
ing committee both contains requisite expertise and is
representative of the broader medical community by
selecting experts from a broad array of backgrounds,
representing different geographic regions, sexes, races,
ethnicities, intellectual perspectives/biases, and scopes
of clinical practice, and by inviting organizations and
professional societies with related interests and ex
pertise to participate as partners or collaborators. The
ACC and AHA have rigorous policies and methods to
ensure that documents are developed without bias or
improper infuence. The complete policy on relation
ships with industry and other entities (RWI) can be
found online.
Beginning in 2017, numerous modifcations to the
guidelines have been and continue to be implemented
to make guidelines shorter and enhance "user friendli
ness." Guidelines are written and presented in a modu
lar knowledge chunk format, in which each chunk in
cludes a table of recommendations, a brief synopsis,
recommendation-specifc supportive text and, when
appropriate, fow diagrams or additional tables. Hyper
linked references are provided for each modular knowl
edge chunk to facilitate quick access and review. More
structured guidelines-including word limits ("tar
gets") and a web guideline supplement for useful but
noncritical tables and fgures-are 2 such changes. This
Preamble is an abbreviated version, with the detailed
version available online.
Glenn N. Levine, MD, FACC, FAHA
Chair, ACC/AHA Task Force on Clinical Practice
Guidelines
Table 1. ERC Questions
Question
Section
Number
In adults >=20 years of age with clinical atherosclerotic
disease (eg, CHD, peripheral artery disease, or CVD)
or at high-risk of ASCVD, what are the magnitude
of beneft (absolute reduction; NNT) in individual
endpoints and composite ischemic events (eg, fatal
cardiovascular event, nonfatal MI, nonfatal stroke,
unstable angina/revascularization) and magnitude of
harm (absolute increase; NNH) in terms of adverse
events (eg, cancer, rhabdomyolysis, diabetes mellitus)
derived from LDL-C lowering in large RCTs (>1000
participants and originally designed to last >12 months)
with statin therapy plus a second lipid-modifying agent
compared with statin alone?
4.1
Clinical atherosclerotic cardiovascular disease (ASCVD) includes acute
coronary syndrome (ACS), those with history of myocardial infarction (MI),
stable or unstable angina or coronary or other arterial revascularization,
stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD)
including aortic aneurysm, all of atherosclerotic origin.
ASCVD indicates atherosclerotic cardiovascular disease; CHD, coronary
heart disease; CVD, cardiovascular disease; ERC, Evidence Review Committee;
LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NNH,
number needed to harm; NNT number needed to treat; and RCT, randomized
controlled trial.
1. INTRODUCTION
1.1. Methodology and Evidence Review
The recommendations listed in the present guideline
are, whenever possible, evidence based. An initial ex
tensive evidence review, which included literature de
rived from research involving human subjects, published
in English, and indexed in MEDLINE (through PubMed),
EMBASE, the Cochrane Library, the Agency for Health
care Research and Quality, and other selected databases
relevant to the present guideline, was conducted from
May 1980 to July 2017. Key search words included
but were not limited to the following: hyperlipidemia,
cholesterol, LDL-C, HDL-C, ezetimibe, bile acid seques
trants, PCSK9 inhibitors, lifestyle, diet, exercise, medica
tions, child, adolescent, screening, primary prevention,
secondary prevention, cardiovascular disease, coronary
artery calcium, familial hypercholesterolemia. ASCVD
risk-enhancing factors, statin therapy, diabetes melli
tus, women, adherence, Hispanic/Latino, South Asian,
African American. Additional relevant studies published
through August 2018 during the guideline writing pro
cess, were also considered by the writing committee
and added to the evidence tables when appropriate.
The fnal evidence tables are included in the Online
Data Supplement and summarize the evidence used by
the writing committee to formulate recommendations.
References selected and published in the present docu
ment are representative and not all-inclusive.
As noted in the detailed version of the Preamble, an
independent evidence review committee was commis
sioned to perform a formal systematic review of critical
clinical questions related to cholesterol (Table 1), the
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results of which were considered by the writing com
mittee for incorporation into the present guideline.
Concurrent with this process, writing committee mem
bers evaluated study data relevant to the rest of the
guideline. The fndings of the evidence review commit
tee and the writing committee members were formally
presented and discussed, and then recommendations
were developed. The systematic review for the 2018
Cholesterol Clinical Practice GuidelinesS1.1-1 is published
in conjunction with the present guideline, and includes
its respective data supplements.
Numerical values for triglycerides, total cholesterol
(TC), low-density lipoprotein cholesterol (LDL-C), high-
density lipoprotein cholesterol (HDL-C), and non-HDL
C are given in both mg/dL and mmol/L. To convert to
mmol/L, the values in mg/dL for TC, LDL-C, HDL-C, and
non-HDL-C were divided by 38.6 and for triglycerides,
by 88.6.
On May 10, 2018 a writing committee member
discussed their participation in an industry-supported,
multicenter study, which they had thought was not rel
evant to this prevention guideline. However, when this
was reviewed using specifc ACC/AHA criteria it was
considered to represent a relevant relationship with in
dustry. Given the current policy that a prevention guide
line writing committee member must be free of any
relevant relationships with industry, this member was
removed from the committee. The 2 sections authored
by the writing committee member were removed and
replaced by new material written by the guideline
chairs, and the revised sections reviewed and approved
by all remaining writing committee members. The writ
ing committee member did not participate in any fur
ther guideline discussions or review of the manuscript
or recommendations.
1.2. Organization of the Writing
Committee
The writing committee consisted of medical experts
including cardiologists, internists, interventionalists, a
nurse practitioner, pharmacists, a physician assistant,
a pediatrician, a nephrologist, and a lay/patient repre
sentative. The writing committee included represen
tatives from the American Heart Association (AHA),
American College of Cardiology (ACC), American
Association of Cardiovascular and Pulmonary Reha
bilitation (AACVPR), American Association Academy
of Physician Assistants (AAPA), Association of Black
Cardiologists (ABC), American College of Preventive
Medicine (ACPM), American Diabetes Association
(ADA), American Geriatrics Society (AGS), American
Pharmacists Association (APhA), American Society
for Preventive Cardiology (ASPC), National Lipid As
sociation (NLA), and Preventive Cardiovascular Nurses
Association (PCNA). Appendix 1 of the present docu
ment lists writing committee members' relevant re
lationships with industry and other entities. For the
purposes of full transparency, the writing committee
members' comprehensive disclosure information is
available online.
1.3. Document Review and Approval
This document was reviewed by 21 offcial reviewers
each nominated by the ACC, AHA, AAPA, ABC, ACPM,
ADA, AGS, APhA, ASPC, NLA, and PCNA, as well as 27
individual content reviewers. Reviewers' RWI informa
tion was distributed to the writing committee and is
published in this document (Appendix 2).
This document was approved for publication by the
governing bodies of the AHA, the ACC, AAPA, ABC,
ACPM, ADA, AGS, APhA, ASPC, NLA, and PCNA.
1.4. Scope of the Guideline
The purpose of the present guideline is to address the
practical management of patients with high blood
cholesterol and related disorders. The writing com
mittee reviewed previously published guidelines, evi
dence reviews, and related statements. Table S1 in the
Web Supplement contains a list of publications and
statements deemed pertinent. The primary sources of
evidence are randomized controlled trials (RCTs). Most
RCTs in this area have been performed with statins
as the only cholesterol-lowering drug.S1.4-1-S1.4-3 Since
the 2013 ACC/AHA cholesterol guideline,S1.4-4 newer
cholesterol-lowering agents (nonstatin drugs) have
been introduced and subjected to RCTs. They include
ezetimibe and PCSK9 inhibitors, and their use is lim
ited mainly to secondary prevention in patients at very
high-risk of new atherosclerotic cardiovascular disease
(ASCVD) events. Most other patients with ASCVD
are treated with statins alone. In primary prevention,
statins are recommended for patients with severe hy
percholesterolemia and in adults 40 to 75 years of
age either with diabetes mellitus or at higher ASCVD
risk. Throughout these guidelines similar to the 2013
guidelines, consistent attention is given to a clinician-
patient risk discussion for making shared decisions.
Besides major risk factors of the pooled cohort equa
tions (PCE), the clinician-patient risk discussion can in
clude other risk-enhancing factors, and when risk sta
tus is uncertain, a coronary artery calcium (CAC) score
is an option to facilitate decision-making in adults
>=40 years of age. In children, adolescents, and young
adults, identifying those with familial hypercholester
olemia (FH) is a priority. However, most attention is
given to reducing lifetime ASCVD risk through lifestyle
therapies.

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CLINICAL STATEMENTS
AND GUIDELINES

1.5. Class of Recommendation and Level
of Evidence
Recommendations are designated with both a class of
recommendation (COR) and a level of evidence (LOE).
The class of recommendation indicates the strength of
recommendation, encompassing the estimated magni
tude and certainty of beneft in proportion to risk. The
level of evidence rates the quality of scientifc evidence
supporting the intervention on the basis of the type,
quantity, and consistency of data from clinical trials and
other sources (Table 2).S1.5-1
1.6. Abbreviations
Abbreviation
Meaning/Phrase
ABI
ankle-brachial index
ACS
acute coronary syndrome
AIDS
acquired immunodefciency syndrome
apoB
apolipoprotein B
ARR
absolute risk reduction
ASCVD
atherosclerotic cardiovascular disease
CAC
coronary artery calcium
CHD
coronary heart disease
CK
creatine kinase
CKD
chronic kidney disease
COR
Class of Recommendation
CTT
Cholesterol Treatment Trialists
CVD
cardiovascular disease
eGFR
estimated glomerular fltration rate
FH
familial hypercholesterolemia
HDL
high-density lipoprotein
HF
heart failure
HIV
human immunodefciency virus
LDL-C
low-density lipoprotein cholesterol
LOE
Level of Evidence
Lp(a)
lipoprotein (a)
MI
myocardial infarction
PCE
pooled cohort equations
QALY
quality-adjusted life-year
RA
rheumatoid arthritis
RCT
randomized controlled trials
RRR
relative risk reduction
RWI
relationships with industry and other entities
SAMS
statin-associated muscle symptoms
SR
systematic review
TC
total cholesterol
VLDL
very low-density lipoprotein
VLDL-C
very low-density lipoprotein cholesterol
2. HIGH BLOOD CHOLESTEROL AND
ASCVD
2.1. Serum Cholesterol, Lipoproteins, and
ASCVD
2.1.1. Cholesterol, Lipoproteins, and
Apolipoprotein B
Serum cholesterol and its lipoprotein carriers (LDL, very
low-density lipoprotein [VLDL], and HDL) are known
to be related to ASCVD. LDL-C is the dominant form
of atherogenic cholesterol. VLDL is the chief carrier of
triglycerides, and VLDL cholesterol (VLDL-C) is also ath
erogenic. HDL-C is seemingly not atherogenic. Chylo
microns transport dietary fat; chylomicron atherogenici
ty is uncertain. The combination of LDL-C and VLDL-C is
called non-HDL-C and is more atherogenic than either
lipoprotein alone. The main protein embedded in LDL
and VLDL is apolipoprotein B (apoB), and like non-HDL
C, apoB is a stronger indicator of atherogenicity than
LDL-C alone.
2.1.2. Cholesterol, LDL-C, and ASCVD
Evidence that serum cholesterol contributes to ASCVD
comes from several sources: animal studies, genetic
forms of hypercholesterolemia, epidemiological stud
ies, and RCTs. US population studiesS2.1.2-1,S2.1.2-2 suggest
that optimal total cholesterol levels are about 150 mg/
dL (3.8 mmol/L), which corresponds to an LDL-C level
of about 100 mg/dL (2.6 mmol/L). Adult populations
with cholesterol concentrations in this range manifest
low rates of ASCVD.S2.1.2-3 RCTs of cholesterol-lowering
drugs in high-risk patients confrm that LDL-C lowering
produces marked reductions in ASCVD. This confrms
the general principle that "lower is better" for LDL
C.S2.1.2-4-S2.1-6 The present guideline looks to evidence
from new RCTs to aid in the translation of RCT data to
the individual patient to provide net beneft.S2.1.2-7
2.1.3. LDL-C and Other Risk Factors
Although LDL-C is a primary cause of atherosclero
sis, other risk factors contribute, as well. The major
risk factors include cigarette smoking, hypertension,
dysglycemia, and other lipoprotein abnormalities. Be
cause atherosclerosis progresses with advancing age,
a person's age also counts as a risk factor. By combin
ing all major risk factors into a prediction equation, an
individual's probability of developing ASCVD can be
estimated. The Framingham Heart StudyS2.1.3-1 took the
lead in creating risk-prediction equations. These were
improved in the 2013 ACC/AHA cholesterol guideli
nesS2.1.3-2 by compiling data from 5 community-based
cohorts that were broadly representative of the US
population. These so-called population cohort equa
tions have been validated in a large community-based
US population.S2.1.3-3 Initially, data from the Women's
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Table 2. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient
Care* (Updated August 2015)
Health Initiative, a contemporary multiethnic cohort
of postmenopausal women, appeared to indicate that
these pooled cohort equations overestimated ASCVD
risk. However, when event surveillance was improved
by data from Centers for Medicare & Medicaid Servic
es, the authors found that the equations discriminated
risk well.S2.1.3-4
Several other factors associate with ASCVD, and in
the present document these are called risk-enhancing
factors. Projections of future risk derived from major
risk factors and risk-enhancing factors can be used to
adjust the intensity of LDL-lowering therapy.
2.2. Measurements of LDL-C
and Non-HDL-C
Recommendations for Measurements of LDL-C and Non-HDL-C
Referenced studies that support recommendations are summarized
in Online Data Supplement 1.
COR
LOE
Recommendations
I
B-NR
1. In adults who are 20 years of age or
older and not on lipid-lowering therapy,
measurement of either a fasting or a
nonfasting plasma lipid profle is effective
in estimating ASCVD risk and documenting
baseline LDL-C.S2.2-1-S2.2-6

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CLINICAL STATEMENTS
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Recommendations for Measurements of LDL-C and Non-HDL-C
(Continued)
COR
LOE
Recommendations
I
B-NR
2. In adults who are 20 years of age or older
and in whom an initial nonfasting lipid profle
reveals a triglycerides level of 400 mg/dL or
higher (>=4.5 mmol/L), a repeat lipid profle
in the fasting state should be performed for
assessment of fasting triglyceride levels and
baseline LDL-C.S2.2-1-S2.2-4
IIa
C-LD
3. For adults with an LDL-C level less than
70 mg/dL (<1.8 mmol/L), measurement of
direct LDL-C or modifed LDL-C estimate is
reasonable to improve accuracy over the
Friedewald formula.S2.2-7-S2.2-9
IIa
C-LD
4. In adults who are 20 years of age or older
and without a personal history of ASCVD,
but with a family history of premature
ASCVD or genetic hyperlipidemia,
measurement of a fasting plasma lipid
profle is reasonable as part of an initial
evaluation to aid in the understanding and
identifcation of familial lipid disorders.
Synopsis
The standard calculation method for LDL-C is the
Friedewald formula: LDL-C=(TC)-(triglycerides/5)-
(HDL-C). When triglyceride levels are not elevated,
this equation is suffciently accurate. In hypertri
glyceridemia, however, Friedewald-calculated LDL
C can be erroneous. After normal food intake,
LDL-C differs minimally with time.S2.2-10 Fasting and
nonfasting TC and HDL-C levels appear to have fairly
similar prognostic value and associations with CVD
outcomes.S2.2-1-S2.2-6,S2.2-11 Thus, nonfasting samples can
be used for risk assessment in primary prevention and
for assessment of baseline LDL-C levels before the ini
tiation of a statin in primary and secondary prevention.
If more precision is necessary, fasting lipids can be mea
sured, but a nonfasting sample is reasonable for most
situations. The unreliability of the Friedewald-calculated
LDL-C levels appears to be greatest at lower levels of
LDL-C, particularly <70 mg/dL (<1.8 mmol/L).S2.2-7 Mar
tin et al. have validated an approach to estimating LDL
C levels from a standard lipid panel when LDL-C levels
is <70 mg/dL (<1.8 mmol/L) and triglycerides levels are
>150 mg/dL (>1.7 mmol/L).S2.2-7-S2.2-9
Recommendation-Specifc Supportive
Text
1. If an individual has ingested an extremely high-fat
meal in the preceding 8 hours, it may be prudent
to assess lipids on another day after counseling
the patient to avoid such meals. Documentation
of the baseline LDL-C level will be useful in
assessing the patient's response to the initiation
of statin therapy, if that is undertaken.S2.2-1-S2.2-6
Similarly, given relatively modest differences in
LDL-C levels associated with the postprandial
state, use of a nonfasting sample is effective
to document baseline lipid levels before initia
tion of statin therapy in individuals with clinical
ASCVD.S2.2-1-S2.2-6 In adults with a family history
of premature ASCVD or genetic hyperlipidemia,
a fasting lipid profle is reasonable for initial
evaluation.
2. Given relatively modest differences in LDL-C lev
els between fasting and non-fasting samples,
the latter is generally adequate to document
baseline lipid levels prior to initiation of statin
therapy.S2.2-1-S2.2-6
3. The unreliability of the Friedewald-calculated
LDL-C levels rises at lower levels of LDL-C, par
ticularly <70 mg/dL (<1.8 mmol/L). If accurate
measurements of LDL-C levels are needed at
very low LDL-C, calculation adjustments can be
used.S2.2-7-S2.2-9 Measurement of apoB may be use
ful in determining whether hypertriglyceridemia is
an atherogenic condition.S2.2-12,S2.2-13
4. In adults with a family history of premature
ASCVD or genetic hyperlipidemia, a fasting lipid
profle is reasonable for initial evaluation to aid
in the understanding and identifcation of familial
lipid disorders.S2.2-12,S2.2-13
2.3. Measurements of Apolipoprotein B
and Lipoprotein (a)
Two lipoprotein entities related to LDL-C are apoB and
lipoprotein (a) [Lp(a)]. Because apoB is the major apoli
poprotein embedded in LDL and VLDL, several investiga
tors identify strength of association between apoB and
ASCVD.S2.3-1 Others report a high correlation between
apoB and non-HDL-C.S2.3-2 Under certain circumstanc
es, particularly in patients with hypertriglyceridemia,
the measurement of apoB may have advantages.S2.3-3
Nevertheless, apoB measurement carries extra expense,
and its measurement in some laboratories may not be
reliable.S2.3-4 A relative indication for its measurement
would be triglyceride >=200 mg/dL. A level >130 mg/dL
corresponds to an LDL-C level >=160 mg/dL and consti
tutes a risk-enhancing factor. A persistent elevation of
apoB can be considered a risk-enhancing factor. Sepa
rately, Lp(a) is a modifed form of LDL that appears to
possess atherogenic potential.S2.3-5 Relative indications
for its measurement are family history of premature
ASCVD or personal history of ASCVD not explained by
major risk factors. Lp(a) increases ASCVD risk especially
at higher levels. Thus, if a decision is made to measure
Lp(a), an Lp(a) >=50 mg/dL or >=125 nmol/L, Lp(a) may
be considered a risk-enhancing factor.S2.3-6 Current evi
dence shows that it should be considered in women
only in the presence of hypercholesterolemia and
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with the understanding that the improvement in risk
prediction in adult women in a large clinical trial was
minimal.S2.3-7 In the present document, an elevation of
Lp(a) is considered to be a risk-enhancing factor.S2.3-6
This is especially in those with higher Lp(a) values and,
if used in women, only in the presence of hypercholes
terolemia.S2.3-7
2.4. Monitoring Response of LDL-C to
Statin Therapy
In large RCTs of cholesterol-lowering therapy, LDL-C
lowering has been consistently shown to reduce the
risk of ASCVD. One large meta-analysisS2.4-1 of statin
clinical trials showed a progressive reduction in risk of
major ASCVD events with lower on-treatment LDL-C
levels. In another larger meta-analysisS2.4-2 of 14 statin
trials, it was observed that a 38.7-mg/dL (1-mmol/L)
reduction of LDL-C levels is accompanied by a 21%
reduction in ASCVD risk. In clinical practice, howev
er, absolute responses in LDL-C to statin therapy de
pend on baseline LDL-C concentrations. A given dose
of statins produces a similar percentage reduction in
LDL-C levels across a broad range of baseline LDL
C levels. For this reason, a more reliable indicator of
statin effcacy is percentage reduction. In the present
document, the percentage reduction is used in follow
up monitoring of patients to estimate the effcacy of
statin therapy. As a rough guide, a lowering of LDL-C
levels of 1% gives an approximate 1% reduction in
the risk of ASCVD- somewhat more at higher base
line LDL-C levels and somewhat less at lower baseline
levels.S2.4-1
3. THERAPEUTIC MODALITIES
3.1. Lifestyle Therapies
3.1.1. Diet Composition, Weight Control, and
Physical Activity
For many years, the AHA and ACC have recommend
ed essentials of a healthy diet for the general public
and for patients at risk for ASCVD. The current docu
ment supports evidence-based recommendations pro
vided in the 2013 AHA/ACC guidelines on lifestyle
management.S3.1.1-1,S3.1.1-2 Patients should consume a
dietary pattern that emphasizes intake of vegetables,
fruits, whole grains, legumes, healthy protein sources
(low-fat dairy products, low-fat poultry (without the
skin), fsh/seafood, and nuts), and nontropical vegetable
oils; and limits intake of sweets, sugar-sweetened bev
erages, and red meats. This dietary pattern should be
adjusted to appropriate calorie requirements, personal
and cultural food preferences, and nutritional therapy
for other medical conditions including diabetes. Caloric
intake should be adjusted to avoid weight gain, or in
overweight/obese patients, to promote weight loss. In
general, adults should be advised to engage in aerobic
physical activity 3-4 sessions per week, lasting on aver
age 40 minutes per session and involving moderate-to
vigorous-intensity physical activity.
3.1.2. Lifestyle Therapies and Metabolic
Syndrome
Lifestyle therapies are particularly indicated for the
metabolic syndrome, which is a cluster of risk factors
associated with an increased risk of ASCVD, diabetes
mellitus, and all-cause death.S3.1.2-1,S3.1.2-2 Metabolic
syndrome is a risk-enhancing factor for ASCVD. The
most widely used clinical defnition of metabolic syn
drome is that proposed by an international consortium
of cardiovascular and diabetes organizations.S3.1.2-3 The
diagnosis is made by the presence of any 3 of the fol
lowing 5 risk factors: elevated waist circumference,
elevated serum triglycerides, reduced HDL-C, elevated
blood pressure, and elevated fasting glucose (Table S2
in the Web Supplement). Metabolic syndrome is closely
linked to excess weight and particularly to abdominal
obesity.S3.1.2-4 Therefore, the prevalence of metabolic
syndrome has risen sharply among both adults and
children as levels of overweight and obesity have risen.
Metabolic syndrome is now found in approximately
one-third of the adults in the United StatesS3.1.2-5 and is
likely underrecognized because of insuffcient rates of
screening. The prevalence of metabolic syndrome in
creases with age and very commonly occurs in patients
with type 2 diabetes mellitus. See Table S2 in the Web
Supplement.
3.2. Lipid-Lowering Drugs
Among lipid-lowering drugs, statins are the cornerstone
of therapy, in addition to healthy lifestyle interventions.
Other LDL-lowering drugs include ezetimibe, bile acid
sequestrants, and PCSK9 inhibitors. Triglyceride-lower
ing drugs are fbrates and niacin; they have a mild LDL-
lowering action, but RCTs do not support their use as
add-on drugs to statin therapy.S3.2-1 Characteristics of
LDL-lowering drugs are summarized in Table S3 in the
Web Supplement.
3.2.1. Statin Therapy
The intensity of statin therapy is divided into 3 cat
egories: high-intensity, moderate-intensity, and low
intensity.S3.2.1-1 High-intensity statin therapy typically
lowers LDL-C levels by >=50%, moderate-intensity
statin therapy by 30% to 49%, and low-intensity statin
therapy by <30% (Table 3). Of course, the magnitude
of LDL-C lowering will vary in clinical practice.S3.2.1-2
Certain Asian populations may have a greater re
sponse to certain statins.S3.2.1-18 Pharmacokinetic pro
fles among statins are heterogeneous (Table S4 in the
Web Supplement). Statin safety has been extensively

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Table 3. High-, Moderate-, and Low-Intensity Statin Therapy*
High Intensity
Moderate Intensity
Low Intensity
LDL-C
lowering
>=50%
30%-49%
<30%
Statins
Atorvastatin
(40 mg) 80 mg
Rosuvastatin 20
mg (40 mg)
Atorvastatin 10 mg
(20 mg)
Rosuvastatin (5 mg)
10 mg
Simvastatin 20-40
mg
Simvastatin
10 mg
...
Pravastatin 40 mg
(80 mg)
Lovastatin 40 mg
(80 mg)
Fluvastatin XL 80 mg
Fluvastatin 40 mg
BID
Pitavastatin 1-4 mg
Pravastatin
10-20 mg
Lovastatin 20
mg
Fluvastatin
20-40 mg
Percent LDL-C reductions with the primary statin medications used in
clinical practice (atorvastatin, rosuvastatin, simvastatin) were estimated
using the median reduction in LDL-C from the VOYAGER database.S3.2.1-2
Reductions in LDL-C for other statin medications (fuvastatin, lovastatin,
pitavastatin, pravastatin) were identifed according to FDA-approved product
labeling in adults with hyperlipidemia, primary hypercholesterolemia, and
mixed dyslipidemia.S3.2.1-4 Boldface type indicates specifc statins and doses
that were evaluated in RCTs,S3.2.1-3,S3.2.1-5-S3.2.1-16 and the Cholesterol Treatment
Trialists' 2010 meta-analysis.S3.2.1-17 All these RCTs demonstrated a reduction in
major cardiovascular events.
*Percent reductions are estimates from data across large populations.
Individual responses to statin therapy varied in the RCTs and should be
expected to vary in clinical practice.S3.2.1-2
LDL-C lowering that should occur with the dosage listed below each
intensity.
Evidence from 1 RCT only: down titration if unable to tolerate atorvastatin
80 mg in the IDEAL (Incremental Decrease through Aggressive Lipid Lowering)
study.S3.2.1-3
Although simvastatin 80 mg was evaluated in RCTs, initiation of
simvastatin 80 mg or titration to 80 mg is not recommended by the FDA
because of the increased risk of myopathy, including rhabdomyolysis.
BID indicates twice daily; FDA, US Food and Drug Administration; LDL-C,
low-density lipoprotein cholesterol; RCT, randomized controlled trial;
VOYAGER, an indiVidual patient data meta-analysis Of statin therapY in At
risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin; and XL,
extended release.
evaluated.S3.2.1-19 Statin-associated side effects are dis
cussed in Section 5. Common medications that may
potentially interact with statins are listed in Table S5
in the Web Supplement. More information on statin
drug-drug interactions can be obtained from the ACC
LDL-C Manager.S3.2.1-20
3.2.2. Nonstatin Therapies
Ezetimibe is the most commonly used nonstatin agent.
It lowers LDL-C levels by 13% to 20% and has a low in
cidence of side effects.S3.2.2-1,S3.2.2-2 Bile acid sequestrants
reduce LDL-C levels by 15% to 30% depending on the
dose. Bile acid sequestrants are not absorbed and do
not cause systemic side effects, but they are associated
with gastrointestinal complaints (eg, constipation) and
can cause severe hypertriglyceridemia when fasting tri
glycerides are >=300 mg/dL (>=3.4 mmol/L). PCSK9 inhibi
tors are powerful LDL-lowering drugs. They generally
are well tolerated, but long-term safety remains to be
proven.S3.2.2-4-S3.2.2-6 Two categories of triglyceride-lower
ing drugs, niacin and fbrates, may also mildly lower
LDL-C levels in patients with normal triglycerides. They
may be useful in some patients with severe hypertri
glyceridemia, but in the present document they are not
listed as LDL-lowering drugs. See Table S4 in the Web
Supplement.
3.2.3. Nonstatin Add-on Drugs to Statin Therapy
Under certain circumstances, nonstatin medications
(ezetimibe, bile acid sequestrants, and PCSK9 inhibi
tors) may be useful in combination with statin therapy.
The addition of a bile acid sequestrant or ezetimibe to a
statin regimen increases the magnitude of LDL-C lower
ing by approximately 15% to 30% and 13% to 20%,
respectively.S3.2.3-1,S3.2.3-2 The addition of a PCSK9 inhibi
tor to a statin regimen has been shown to further re
duce LDL-C levels by 43% to 64%.S3.2.3-3,S3.2.3-4 See Table
S5 in the Web Supplement.
4. PATIENT MANAGEMENT GROUPS
4.1. Secondary ASCVD Prevention
Recommendations for Statin Therapy Use in Patients With ASCVD
Referenced studies that support recommendations are summarized
in Online Data Supplements 6 to 8 and in the Systematic Review
Report.
COR
LOE
Recommendations
I
A
1. In patients who are 75 years of age or
younger with clinical ASCVD,* high-
intensity statin therapy should be initiated or
continued with the aim of achieving a 50%
or greater reduction in LDL-C levels.S4.1-1-S4.1-5
I
A
2. In patients with clinical ASCVD in
whom high-intensity statin therapy is
contraindicated or who experience
statin-associated side effects, moderate-
intensity statin therapy should be initiated
or continued with the aim of achieving
a 30% to 49% reduction in LDL-C
levels.S4.1-3,S4.1-6-S4.1-13
I
B-NR
3. In patients with clinical ASCVD who are
judged to be very high risk and considered
for PCSK9 inhibitor therapy, maximally
tolerated LDL-C lowering therapy should
include maximally tolerated statin therapy
and ezetimibe.S4.1-14,S4.1-15
IIa
ASR
4. In patients with clinical ASCVD who are
judged to be very high risk and who are on
maximally tolerated LDL-C lowering therapy
with LDL-C 70 mg/dL or higher (>=1.8
mmol/L) or a non-HDL-C level of 100 mg/dL
or higher (>=2.6 mmol/L), it is reasonable to
add a PCSK9 inhibitor following a clinician-
patient discussion about the net beneft,
safety, and cost.S4.1-15-S4.1-19
IIa
B-R
5. In patients with clinical ASCVD who are on
maximally tolerated statin therapy and are
judged to be at very high risk and have an
LDL-C level of 70 mg/dL or higher (>=1.8
mmol/L), it is reasonable to add ezetimibe
therapy.S4.1-14,S4.1-15
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Recommendations for Statin Therapy Use in Patients With ASCVD
(Continued)
COR
LOE
Recommendations
Value Statement: Low
Value (LOE: B-NR)
6. At mid-2018 list prices, PCSK9 inhibitors
have a low cost value (>$150000 per QALY)
compared to good cost value (<$50000 per
QALY) (Section 7 provides a full discussion
of the dynamic interaction of different prices
and clinical beneft).S4.1-20-S4.1-22
IIa
B-R
7. In patients older than 75 years of age with
clinical ASCVD, it is reasonable to initiate
moderate- or high-intensity statin therapy
after evaluation of the potential for ASCVD
risk reduction, adverse effects, and drug-
drug interactions, as well as patient frailty
and patient preferences.S4.1-23-S4.1-31
IIa
C-LD
8. In patients older than 75 years of age who
are tolerating high-intensity statin therapy,
it is reasonable to continue high-intensity
statin therapy after evaluation of the
potential for ASCVD risk reduction,
adverse effects, and drug-drug interactions,
as well as patient frailty and patient
preferences.S4.1-3,S4.1-10,S4.1-23,S4.1-26,S4.1-31-S4.1-36
IIb
B-R
9. In patients with clinical ASCVD who are
receiving maximally tolerated statin therapy
and whose LDL-C level remains 70 mg/dL or
higher (>=1.8 mmol/L), it may be reasonable
to add ezetimibe.S4.1-15
IIb
B-R
10. In patients with heart failure (HF) with
reduced ejection fraction attributable
to ischemic heart disease who have a
reasonable life expectancy (3 to 5 years)
and are not already on a statin because of
ASCVD, clinicians may consider initiation of
moderate-intensity statin therapy to reduce
the occurrence of ASCVD events.S4.1-37
*Clinical atherosclerotic cardiovascular disease (ASCVD) includes acute
coronary syndrome (ACS), those with history of myocardial infarction (MI),
stable or unstable angina or coronary or other arterial revascularization,
stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD)
including aortic aneurysm, all of atherosclerotic origin.
Synopsis
Clinical ASCVD encompasses ACS, those with history
of MI, stable or unstable angina or coronary or other
arterial revascularization, stroke, TIA or PAD including
aortic aneurysm, all of atherosclerotic origin. The writ
ing group used primarily the Cholesterol Treatment Tri
alists' (CTT) meta-analysisS4.1-3,S4.1-4 of statin RCTs plus
4 other RCTs.S4.1-1,S4.1-2,S4.1-38,S4.1-45 Additional RCTs have
used nonstatin drugs as add-ons to statin therapy and
are included here. As a primary recommendation, high-
intensity statin therapy is indicated for clinical ASCVD,
but if this cannot be used, moderate-intensity statin
therapy can be initiated (Figure 1). The frst goal is to
achieve a >=50% reduction in LDL-C levels, but if LDL-C
levels remains >=70 mg/dL (>=1.8 mmol/L) on maximally
tolerated statin therapy, adding ezetimibe may be rea
sonable. In patients >75 years of age with ASCVD, po
tential benefts versus adverse effects of statin therapy
should be considered before initiation of statin therapy.
Finally, in very high-risk patients with multiple high-risk
clinical factors, ezetimibe can be added to maximally
tolerated statin therapy. Furthermore, if LDL-C levels
remain >=70 mg/dL (>=1.8 mmol/L), adding a PCSK9 in
hibitor is reasonable if the cost/beneft ratio is favor
able. In patients with HF due to ischemic heart disease,
moderate-intensity statins may be considered.
Recommendation-Specifc Supportive
Text
1. CTT meta-analysisS4.1-3,S4.1-4 showed that LDL-C
lowering with statins reduces major ASCVD
events. Patients with strokeS4.1-1 or peripheral
artery diseaseS4.1-5 also derive these benefts. In
a meta-analysis of 5 RCTs,S4.1-3 high-intensity
statins compared with moderate-intensity statin
therapy, signifcantly reduced major vascular
events by 15% with no signifcant reduction in
coronary deaths. Large absolute LDL-C reduction
was associated with a larger proportional reduc
tion in major vascular events.S4.1-4 High-intensity
statin therapy generally reduces LDL-C levels by
>=50%. This percentage can be used to judge
clinical effcacy. Absolute beneft from statin ther
apy depends on baseline LDL-C levels; the great
est absolute beneft accrues to patients with the
highest baseline LDL-C levels. Percentage reduc
tion of LDL-C levels is the most effcient means
to estimate expected effcacy. An alternative to
evaluating adequacy of therapy is to examine
LDL-C on maximum-intensity statins. In a patient
with ASCVD, if LDL-C level is >=70 mg/dL (>=1.8
mmol/L), adding ezetimibe may be reasonable
(see Recommendation 3).
2. Moderate-intensity statin therapy also reduces
major vascular events and coronary heart disease
(CHD) deaths in patients with ASCVD.S4.1-6,S4.1-7,
S4.1-9-S4.1-13,S4.1-40 In RCTs, most of which included
moderate-intensity statin therapy, there was a
signifcant reduction in major vascular events
even among those >75 years of age. Therefore,
an upper age cutoff for moderate-intensity
statin therapy was not identifed in patients with
ASCVD.
3. Patients with clinical ASCVD who are judged to
be very high risk include those with a history of
multiple major ASCVD events or 1 major ASCVD
event and multiple high-risk conditions (Table 4).
In these patients, additional net beneft from fur
ther LDL-C lowering when LDL-C is >=70 mg/dL
(>=1.8 mmol/L) or non-HDL-C >=100 mg/dL (>=2.6
mmol/L) by ezetimibe and 2 PCSK9 inhibitors
(evolocumab and alirocumab) has been dem
onstrated by 3 RCTs.S4.1-15,S4.1-17,S4.1-18 This guide
line makes a strong recommendation (COR I)

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Figure 1. Secondary prevention in patients with clinical ASCVD.
Colors correspond to Class of Recommendation in Table 2. Clinical ASCVD consists of ACS, those with history of MI, stable or unstable angina or coronary other
arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD) including aortic aneurysm, all of atherosclerotic origin. Very
high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions (Table 4). ACS indicates acute coronary
syndrome; ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MI, myocardial
infarction; and PCSK9-I, PCSK9 inhibitor.
for clinicians to add ezetimibe to maximally
tolerated statin therapy as a frst step in lower
ing LDL-C further. Although no RCT specifcally
tested the strategy of ezetimibe frst and then a
PCSK9 inhibitor, ezetimibe was allowed at entry
along with statin therapy in both PCSK9 inhibi
tor trials (FOURIER, ODYSSEY OUTCOMES). Even
so, only very small numbers (3% and 5% respec
tively) were on ezetimibe during these trials. The
strategy of ezetimibe before PCSK9 inhibitor is
recommended because ezetimibe is widely avail
able as a generic drug and has proven safety and
tolerability.S4.1-15 This approach is supported by 2
simulation studies from large populations of very
high-risk patients; these reports showed that
addition of ezetimibe to statin therapy will lower
LDL-C to <70 mg/dL (1.8 mmol/L) in the major
ity of patients, leaving a minority eligible for a
PCSK9 inhibitor.S4.1-42,S4.1-43 These 2 well-designed
simulation studies favor the strategy of addition
of ezetimibe before PCSK9 inhibitor and warrants
an LOE of B-NR.
4. The
FOURIER
trial
(Further
Cardiovascular
Outcomes Research with PCSK9 Inhibition in
Subjects with Elevated Risk) evaluated the PCSK9
inhibitor evolocumab among patients with
ASCVD who met at least 1 major or 2 minor
criteria.S4.1-17 Recruitment was limited to patients
who had LDL-C >=70 mg/dL (>=1.8 mmol/L) (or
non-HDL-C >=100 mg/dL (>=2.6 mmol/L)) on maxi
mal statin  ezetimibe. At a median follow-up
of 2.2 years, evolocumab signifcantly reduced
composite ASCVD (15% RRR; 1.5% AAR) with
out neurocognitive side effects,S4.1-16,S4.1-17 The
ODYSSEY OUTCOMES trial (ODYSSEY Outcomes:
Evaluation of Cardiovascular Outcomes After
an Acute Coronary Syndrome During Treatment
With Alirocumab), tested alirocumab in patients
on maximal statin  ezetimibe with ACS over a
median of 2.8 years, observed a 15% RRR (1.6%

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Table 4. Very High-Risk* of Future ASCVD Events
Major ASCVD Events
Recent ACS (within the past 12 mo)
History of MI (other than recent ACS event listed above)
History of ischemic stroke
Symptomatic peripheral arterial disease (history of claudication with ABI
<0.85, or previous revascularization or amputationS4.1-40)
High-Risk Conditions
Age >=65 y
Heterozygous familial hypercholesterolemia
History of prior coronary artery bypass surgery or percutaneous coronary
intervention outside of the major ASCVD event(s)
Diabetes mellitus
Hypertension
CKD (eGFR 15-59 mL/min/1.73 m2)S4.1-15,S4.1-17
Current smoking
Persistently elevated LDL-C (LDL-C >=100 mg/dL [>=2.6 mmol/L]) despite
maximally tolerated statin therapy and ezetimibe
History of congestive HF
*Very high-risk includes a history of multiple major ASCVD events or one
major ASCVD event and multiple high-risk conditions.
ABI indicates ankle-brachial index; ACS, acute coronary syndrome; ASCVD,
atherosclerotic cardiovascular disease; CKD, chronic kidney disease; eGFR,
estimated glomerular fltration rate; HF, heart failure; LDL, low-density
lipoprotein cholesterol; and MI, myocardial infarction.
ARR) in composite ASCVD events.S4.1-18 Together,
FOURIER and ODYSSEY OUTCOMES justify a COR
of IIa for PCSK9 inhibitors (acknowledging eff
cacy, but at the same time recognizing that there
is limited experience with long-term tolerance
of expensive monoclonal antibodies that is also
inconvenient because it requires repetitive admin
istration via the parenteral route). Because of
the statistically signifcant results in 2 large RCTs
showing reductions in ASCVD events in patients
who had very high risk and LDL-C >=70 mg/dL
(>=1.8 mmol/L) while on maximally tolerated LDL-C
lowering therapy this recommendation warrants
an LOE of A. There are 2 alternative pathways to
initiation of PCSK9 inhibitors: (a) in patients on
maximally tolerated statin + ezetimibe; and (b)
in those on maximally tolerated statin alone. The
strategy of (a) statin + ezetimibe before PCSK9
inhibitor, was graded COR I for reasons given in
Recommendation 3. Second, strategy (b), exclud
ing ezetimibe, would expose more patients to the
inconvenience of antibody therapy and reduce
overall cost effectiveness. If patients develop 2
consecutive LDL-C levels <25 mg/dL while on
a PCSK9 inhibitor, clinical judgment should be
used to determine whether de-intensifcation
of lipid lowering regimen is warranted as long
term safety of such low levels of LDL-C remains
unknown.
5. In IMPROVE-IT (Improved Reduction of Outcomes:
Vytorin Effcacy International Trial),S4.1-15 addi
tion of ezetimibe to moderate-intensity statin
therapy among patients with ACS and LDL-C
levels >=50 mg/dL (>=1.3 mmol/L) resulted in a
signifcant ASCVD risk reduction (7% relative
risk reduction [RRR]; 2% absolute risk reduction
[ARR]) at a median follow-up of 6 years. The
TIMI (Thrombolysis in Myocardial Infarction) Risk
Score for Secondary Prevention (TRS 2 degP) is an
integer-based risk stratifcation tool for patients
with ASCVD. TRS 2 degP includes 9 readily avail
able clinical high-risk features and was initially
developed in a population of patients with MI
within 2 weeks to 1 year of randomization to a
thrombin receptor agonistS4.1-44 and further vali
dated in IMPROVE-IT.S4.1-14 A higher number of
these high-risk features was associated with a
higher risk of recurrent ASCVD events. In post-
ACS patients with >=3 high-risk features, addition
of ezetimibe was associated with substantial risk
reduction (19% RRR; 6.3% ARR; number needed
to treat, 16); those with 2 high-risk features had
some beneft, whereas those with 0 or 1 addi
tional features had no beneft.S4.1-14 Therefore, it
is reasonable to initiate ezetimibe in patients with
ASCVD who are on maximally tolerated statin
therapy and judged to be at very high risk. For the
present guideline, a defnition of very high risk is
amalgamated from TRS 2 degP and the recruitment
criteria of 2 trials with PCSK9 inhibitors (Table 4).
6. The cost-effectiveness of using PCSK9 inhibi
tors for the secondary prevention of ASCVD has
been evaluated in 7 published simulation mod
els, as detailed in Section 7 (and Online Data
Supplements 44 and 45). The reported incremen
tal cost-effectiveness ratios range from $141700
to $450000 per added (QALY), with all but 1
model reporting "low value" (>$150000 per
QALY added). All models agree that the value
provided by PCSK9 inhibitors would be signif
cantly improved by price reductions of 70% to
85% from the mid-2018 US list price of roughly
$14000 a year.
7. When high-intensity stain therapy was compared
with moderate-intensity statin therapy in patients
>75 years of age with ASCVD,S4.1-3 there was
no heterogeneity of effect among age groups
>75, >65 to <=75, and <=65 years. However,
analyses of RCTs that compared statin therapy
(mostly moderate intensity) with placebo among
patients >75 years of age with ASCVD showed
statistically signifcant reduction in major vascu
lar events.S4.1-3 Because older adults may have a
higher risk of adverse events (eg, liver function
test abnormalities), lower statin adherence, and

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higher discontinuation rates with high-intensity
therapy,S4.1-45 a moderate-intensity statin may
be preferable. Nevertheless, the decision to ini
tiate moderate- or high-intensity statin therapy
in patients >75 years of age with ASCVD should
be based on expected beneft versus competing
comorbidities.S4.1-23-S4.1-31
8. This recommendation is based on the observa
tion that the age reported in clinical trials of statin
therapy in patients with ASCVD represents the
patient's age at study entry. Therefore, it is rea
sonable to consider continuation of high-intensity
therapy in patients >75 years of age with ASCVD
if they are tolerating the statin and have a low
risk of competing morbidities.S4.1-23,S4.1-26,S4.1-31
RCTsS4.1-32,S4.1-33,S4.1-35,S4.1-36 have not shown an
adverse effect of statin therapy on cognition.
9. Although
moderate-intensity
statin
therapy
reduces ASCVD events, it is less effective than
high-intensity therapy.S4.1-3 This difference pre
sumably is due to differences in LDL-C-lowering
potency. Hence, if ezetimibe were to be added to
a moderate-intensity therapy to compensate for
the difference in LDL-C-lowering ability between
moderate- and high-intensity statins, the combi
nation of moderate-intensity statin and ezetimibe
could potentially produce a level of ASCVD risk
reduction similar to that produced by high-inten
sity therapy alone. This hypothesis is supported by
the fnding that ezetimibe enhanced risk reduc
tion when combined with moderate-intensity
therapy in patients after ACS.S4.1-15 Thus, it may be
reasonable to add ezetimibe to moderate-inten
sity therapy in patients with ASCVD for whom
high-intensity therapy is indicated but cannot be
used, provided their LDL-C level remains >=70 mg/
dL (>=1.8 mmol/L) on moderate-intensity therapy.
The same reasoning holds for any patient whose
LDL-C level remains >=70 mg/dL (>=1.8 mmol/L) on
maximally tolerated statin therapy
10. The CORONA (Controlled Rosuvastatin Multi
national Trial in Heart Failure) trialS4.1-38 (patients
with ischemic HF and left ventricular ejection
fraction <40%) and GISSI HF trial (Effects of n-3
PUFA and Rosuvastatin on Mortality-Morbidity of
Patients With Symptomatic CHF)S4.1-39 (patients
with ischemic and nonischemic HF, 9.8% with left
ventricular ejection fraction >40%) evaluated the
effcacy and safety of initiation of 10 mg of rosuv
astatin daily compared with placebo. Neither trial
met its primary outcome. Rosuvastatin reduced
the risk of total hospitalizations, hospitalizations
for a cardiovascular cause, and hospitalizations for
worsening HF in CORONA. A subsequent analysis
accounting for repeat HF hospitalizations showed
signifcant reduction in HF hospitalizations.S4.1-46
Post hoc analyses from CORONA showed that
patients randomized to rosuvastatin with less
advanced HF with reduced ejection fraction (low
est tertile of NT-proBNP) had a signifcant reduction
in the primary outcome, but no beneft was seen
among patients with more advanced HF.S4.1-47 The
CORONA and GISSI studies were notable for high
overall and cardiovascular mortality rates, with
MI occurring in a small minority. A subsequent
patient-level analysisS4.1-37 that pooled data from
both these trials and accounted for competing
causes of death showed a signifcant 19% reduc
tion in the risk of MI with rosuvastatin in patients
with ischemic HF, although the ARR was small.
4.2. Severe Hypercholesterolemia
(LDL-C >=190 mg/dL [>=4.9 mmol/L])
Recommendations for Primary Severe Hypercholesterolemia
(LDL-C >=190 mg/dL [>=4.9 mmol/L])
Referenced studies that support recommendations are summarized
in Online Data Supplements 9 and 10.
COR
LOE
Recommendations
I
B-R
1. In patients 20 to 75 years of age with an
LDL-C level of 190 mg/dL or higher (>=4.9
mmol/L), maximally tolerated statin therapy
is recommended.S4.2-1-S4.2-7
IIa
B-R
2. In patients 20 to 75 years of age with
an LDL-C level of 190 mg/dL or higher
(>=4.9 mmol/L) who achieve less than a
50% reduction in LDL-C while receiving
maximally tolerated statin therapy and/
or have an LDL-C level of 100 mg/dL or
higher (>=2.6 mmol/L), ezetimibe therapy is
reasonable.S4.2-8-S4.2-10
IIb
B-R
3. In patients 20 to 75 years of age with a
baseline LDL-C level of 190 mg/dL or higher
(>=4.9 mmol/L), who achieve less than a
50% reduction in LDL-C levels and have
fasting triglycerides 300 mg/dL or lower
(<=3.4 mmol/L), while taking maximally
tolerated statin and ezetimibe therapy, the
addition of a bile acid sequestrant may be
considered.S4.2-11,S4.2-12
IIb
B-R
4. In patients 30 to 75 years of age with
heterozygous FH and with an LDL-C level
of 100 mg/dL or higher (>=2.6 mmol/L)
while taking maximally tolerated statin and
ezetimibe therapy, the addition of a PCSK9
inhibitor may be considered.S4.2-9,S4.2-13-S4.2-15
IIb
C-LD
5. In patients 40 to 75 years of age with
a baseline LDL-C level of 220 mg/dL or
higher (>=5.7 mmol/L) and who achieve
an on-treatment LDL-C level of 130 mg/
dL or higher (>=3.4 mmol/L) while receiving
maximally tolerated statin and ezetimibe
therapy, the addition of a PCSK9 inhibitor
may be considered.S4.2-13-S4.2-17
Value Statement:
Uncertain Value
(B-NR)
6. Among patients with FH without evidence
of clinical ASCVD taking maximally tolerated
statin and ezetimibe therapy, PCSK9
inhibitors provide uncertain value at mid
2018 US list prices.
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Synopsis
Patients with severe hypercholesterolemia have a high
lifetime risk, and decisions about statins in these pa
tients do not require ASCVD risk scoring. These pa
tients derive net ASCVD risk reduction beneft from
interventions that increase expression of LDL receptors.
The strongest data have been derived from statin RCTs,
which have demonstrated greater risk reduction with
statins than with placebo and greater reduction from
higher-intensity statin therapy than with moderate-
intensity statin therapy. Ezetimibe plus a moderate-in
tensity statin is associated with greater LDL-C reduction
than is statin monotherapy in patients with hetero
zygous FH, and the combination reduces ASCVD risk
more than moderate-intensity statin monotherapy in
patients who have had a recent ACS. In selected pa
tients with severe hypercholesterolemia whose LDL-C is
inadequately controlled with drug therapy, LDL apher
esis is an option. Referral to a lipid specialist may be
indicated.
Recommendation-Specifc Supportive
Text
1. Patients with primary severe hypercholesterolemia
(LDL-C levels >=190 mg/dL [>=4.9 mmol/L]) have a
high-risk of ASCVDS4.2-2,S4.2-4,S4.2-18 and premature
and recurrent coronary events.S4.2-3 Although there
have been no randomized, placebo-controlled tri
als of statin therapy done exclusively in subjects
with LDL-C levels >=190 mg/dL (>=4.9 mmol/L),
a placebo-controlled primary prevention study
performed in men with a mean baseline LDL-C
level of 19217 mg/dL (4.90.4 mmol/L) demon
strated a reduced incidence of MI and cardiovas
cular death in those receiving pravastatin 40 mg
daily.S4.2-5 These fndings were extended in a post
hoc analysis of 2560 exclusively primary-preven
tion subjects in that RCT and in a 20-year observa
tional post-trial long-term follow-up study.S4.2-19 In
addition, retrospective cohort studies have dem
onstrated that statin therapy reduces risk of inci
dent MIS4.2-6 and of CHD and all-cause deathS4.2-1
in patients with phenotypic or genetically con
frmed FH. Because moderate- or high-intensity
statins have been shown to reduce ASCVD risk
in both primary- and secondary-prevention trials
and because high-intensity statins provide greater
ASCVD risk reduction than moderate-intensity
statins or placebo,S4.2-7 maximally tolerated statin
therapy should be administered to patients with
primary severe hypercholesterolemia.
2. A large placebo-controlled RCT examined the
effect of simvastatin 80 mg daily, with or without
ezetimibe 10 mg daily, on carotid intima-media
thickness and plasma lipoproteins over 2 years.
Mean LDL-C reduction was greater in the com
bined-therapy group, but there was no difference
in carotid intima-media thickness between the 2
groups. The study was not powered to examine
the risk of ASCVD events.S4.2-10 However, a very
large placebo-controlled RCT examining ASCVD
outcomes in post-ACS patients, performed over
a period of 7 years, showed that the addition
of ezetimibe 10 mg to simvastatin 40 mg daily
resulted in greater ASCVD risk reduction than that
produced by statin monotherapy.S4.2-8 Secondary-
prevention patients with certain ASCVD risk indi
cators exhibit greater ASCVD risk reduction from
ezetimibe therapy than do patients without these
characteristics.S4.2-20 Patients with severe hyper
cholesterolemia who are adherent to statins,
achieve <50% reduction in LDL-C levels with
maximally tolerated statin therapy, and have an
LDL-C level >=100 mg/dL (>=2.6 mmol/L) are likely
to derive additional ASCVD risk reduction from
ezetimibe add-on therapy through additional
LDL-C lowering.S4.2-9
3. When administered to patients with severe hyper
cholesterolemia who are taking maximally toler
ated statins with or without ezetimibe, bile acid
sequestrants have demonstrated LDL-C-lowering
effcacy.S4.2-11,S4.2-12 However, the clinical utility of
bile acid sequestrants is limited by the absence
of ASCVD outcomes data when used in combi
nation with statins, as well as by the issues of
twice-daily dosing, high pill burden, the absence
of well-tolerated generic formulations, drug inter
actions, and the potential for triglyceride eleva
tion. Nonetheless, in patients with very severe
hypercholesterolemia, adding sequestrants to
otherwise maximal cholesterol-lowering therapy
in patients who are not eligible for a PCSK9 inhib
itor may be considered.
4. PCSK9 inhibitors are promising drugs for treat
ment of FH.S4.2-9,S4.2-13-S4.2-15 Two placebo-con
trolled RCTs of the effcacy and safety of PCSK9
inhibitors in patients with heterozygous FH who
were >=18 years of age and taking stable, maxi
mally tolerated statin therapy demonstrated
favorable safety profles and an additional >=50%
reduction in LDL-C.S4.2-10,S4.2-15 There are no cur
rently available outcomes trials of PCSK9 inhibi
tors in patients with ASCVD heterozygous FH.
In patients with LDL-C levels >=190 mg/dL (>=4.9
mmol/L), advancing age is associated with pro
gressively increasing ASCVD risk,S4.2-4 and age-
related risk would likely apply to those with
heterozygous FH because of their higher lifetime
exposure to increased LDL-C concentration.S4.2-18
A long-term prospective cohort registry study of

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2404 patients with heterozygous FH (molecularly
defned) taking contemporary statin with or with
out ezetimibe treatment regimens identifed age
>30 years, male sex, history of ASCVD, high blood
pressure, increased waist circumference, active
smoking, Lp(a) >=50 mg/dL, and LDL-C levels >=100
mg/dL (>=2.6 mmol/L) as independent predictors
of incident ASCVD over a 5.5-year follow-up
period.S4.2-14 Because other medical interventions
that lower LDL-C levels via increased expression
of LDL receptors reduce ASCVD risk,S4.2-9 the use
of PCSK9 inhibitors in selected maximally treated
patients with heterozygous FH with persistently
elevated LDL-C levels may be considered after a
clinician-patient discussion of the net benefts
versus the cost of such therapy.
5. Regardless of whether a patient with LDL-C lev
els >=190 mg/dL (>=4.9 mmol/L) is found to have a
genetic mutation associated with FH, those with
very high LDL-C values are most likely to achieve
the greatest beneft from evidence-based LDL-C-
lowering therapy. Consequently, patients who
have a baseline LDL-C level >=220 mg/dL (>=5.7
mmol/L) and an on-treatment LDL-C level >=130
mg/dL (>=3.4 mmol/L) despite maximally tolerated
statin and ezetimibe therapy may be considered
for treatment with a PCSK9 inhibitor after a clini
cian-patient discussion of the net benefts versus
the costs of such therapy.
6. The cost-effectiveness of PCSK9 inhibitors for
primary prevention among patients with LDL-C
levels >190 mg/dL (>=4.9 mmol/L), or with FH,
has not been evaluated extensively, and their
clinical effectiveness in reducing ASCVD events
in these patients has also not been established.
The 2 published cost-effectiveness models for pri
mary prevention (see Online Data Supplements
44 and 45 and Section 7.) report very different
results, with one suggesting an incremental cost-
effectiveness ratio of $503000 per QALY added,
and the other reporting $75000 per QALY added.
Because of the lack of consistent evidence, the
use of PCSK9 inhibitors has uncertain value for
the primary prevention of ASCVD in patients with
severe hypercholesterolemia.
4.3. Diabetes Mellitus in Adults
Recommendations for Patients With Diabetes Mellitus
Referenced studies that support recommendations are summarized
in Online Data Supplements 11 and 12.
COR
LOE
Recommendations
I
A
1. In adults 40 to 75 years of age with diabetes
mellitus, regardless of estimated 10-year
ASCVD risk, moderate-intensity statin
therapy is indicated.S4.3-1-S4.3-9
Recommendations for Patients With Diabetes Mellitus (Continued)
COR
LOE
Recommendations
IIa
B-NR
2. In adults 40 to 75 years of age with diabetes
mellitus and an LDL-C level of 70 to 189
mg/dL (1.7 to 4.8 mmol/L), it is reasonable
to assess the 10-year risk of a frst ASCVD
event by using the race and sex-specifc PCE
to help stratify ASCVD risk.S4.3-10,S4.3-11
IIa
B-R
3. In adults with diabetes mellitus who have
multiple ASCVD risk factors, it is reasonable
to prescribe high-intensity statin therapy
with the aim to reduce LDL-C levels by 50%
or more.S4.3-12,S4.3-13
IIa
B-NR
4. In adults older than 75 years of age with
diabetes mellitus and who are already on
statin therapy, it is reasonable to continue
statin therapy.S4.3-5,S4.3-8,S4.3-13
IIb
C-LD
5. In adults with diabetes mellitus and 10-year
ASCVD risk of 20% or higher, it may be
reasonable to add ezetimibe to maximally
tolerated statin therapy to reduce LDL-C
levels by 50% or more.S4.3-14,S4.3-15
IIb
C-LD
6. In adults older than 75 years with diabetes
mellitus, it may be reasonable to initiate
statin therapy after a clinician-patient
discussion of potential benefts and
risks.S4.3-5,S4.3-8,S4.3-13
IIb
C-LD
7. In adults 20 to 39 years of age with diabetes
mellitus that is either of long duration (>=10
years of type 2 diabetes mellitus, >=20 years
of type 1 diabetes mellitus), albuminuria
(>=30 mcg of albumin/mg creatinine),
estimated glomerular fltration rate (eGFR)
less than 60 mL/min/1.73 m2, retinopathy,
neuropathy, or ankle-brachial index (ABI;
<0.9), it may be reasonable to initiate statin
therapy.S4.3-5,S4.3-6,S4.3-8,S4.3-16-S4.3-25
Synopsis
Although most adults 40 to 75 years of age with dia
betes mellitus are at intermediate or high-risk of their
frst ASCVD event,S4.3-5,S4.3-6,S4.3-8,S4.3-9 evaluation of AS
CVD risk will help refne risk estimates and therapeu
tic decision-making. Because primary-prevention trials
demonstrate that moderate-intensity statin therapy in
large cohorts with diabetes mellitus provides signifcant
beneft,S4.3-1-S4.3-4,S4.3-7 this treatment is indicated in such
individuals. However, given the increased morbidity
and mortality associated with a frst event in diabetes
mellitus and the residual risk among the statin-treated
groups in these trials, together with the evidence of
beneft from high-intensity statin treatment in primary
prevention among men >50 years of age and women
>60 years of age,S4.3-13 high-intensity statin therapy to
maximize risk reduction is preferred for patients with
diabetes mellitus as they age or if they have risk modi
fers. Adults 20 to 39 years of age are mostly at low
10-year risk, although moderate-intensity statin thera
py in those with long-standing diabetes mellitus or a
concomitant higher-risk condition may be reasonable
(Table 5).S4.3-17,S4.3-20,S4.3-21 Adults >75 years of age with
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Table 5. Diabetes-Specifc Risk Enhancers That Are Independent of
Other Risk Factors in Diabetes Mellitus
Risk Enhancers
Long duration (>=10 years for type 2 diabetes mellitusS4.3-20 or >=20 years
for type 1 diabetes mellitusS4.3-6
Albuminuria >=30 mcg of albumin/mg creatinineS4.3-25
eGFR <60 mL/min/1.73 m2S4.3-25
RetinopathyS4.3-19
NeuropathyS4.3-16
ABI <0.9S4.3-22,S4.3-24
ABI indicates ankle-brachial index; and eGFR, estimated glomerular
fltration rate.
diabetes mellitus are at high-riskS4.3-5,S4.3-8 and clinical
trial evidenceS4.3-26 suggests they are likely to beneft
from continuing or initiating statin therapy, although
this may be compromised by reduced longevity and in
creased adverse events.
Recommendation-Specifc Supportive
Text
1. Most adults 40 to 75 years of age with diabetes
mellitus are at intermediate or high-risk (PCE >=7.5%
10-year risk) of ASCVD events.S4.3-5,S4.3-6,S4.3-8,S4.3-9
Three of 4 double-blinded primary-preven
tion RCTs of moderate statin therapy in large
cohorts with diabetes mellitus in this age
range showed signifcant reductions in ASCVD
events.S4.3-1,S4.3-2,S4.3-4,S4.3-7 A meta-analysis of these
trials found that moderate-intensity statin therapy
is associated with a risk reduction of 25%,S4.3-3
resulting in a risk level similar to that of people
without diabetes mellitus and with no apparent
difference in beneft between type 1 and type
2 diabetes mellitus. Therefore, on the basis of a
high level of evidence, moderate-intensity statin
therapy is indicated in patients 40 to 75 years of
age with diabetes mellitus for primary prevention.
2. Although it is well recognized that the frequency
of a frst ASCVD event in adults with diabetes
mellitus is signifcantly increased compared with
those without diabetes mellitus, there is a wide
spectrum of risk among individuals with diabe
tes mellitusS4.3-5,S4.3-6,S4.3-8,S4.3-9 that varies with age,
duration of diabetes mellitus, and the presence
of traditional risk factors and risk modifers com
mon to the general population, as well as those
specifc to the population with diabetes mellitus
(Table 5). Because the decision to upgrade statin
treatment from moderate to high intensity is
infuenced by the level of ASCVD risk, the PCE
risk estimator in adults 40 to 75 years of age with
diabetes mellitus has utility in refning treatment
decisions in these patients.S4.3-10,S4.3-11 The ASCVD
risk score, however, does not determine whether
statin intensity should be increased. Rather, it
begins an evaluation that includes clinician judg
ment of the individual's global risk, the potential
for beneft from a high-intensity statin versus the
potential for adverse effects or drug-drug interac
tions and evaluation should also include patient
preferences and values.
3. The occurrence of a frst ASCVD event in patients
40 to 75 years of age with diabetes mellitus is
associated with increased morbidity and mortality
compared with those without diabetes mellitus,
which places a particularly high premium on pri
mary prevention in those with diabetes mellitus in
that age range. Although trials using moderate-
intensity statin therapy demonstrate signifcant
beneft in such individuals, the residual risk in the
statin treatment groups in these trials remained
high (eg, 8.5% had major cardiovascular events in
3.8 years).S4.3-3 Strong general evidence indicates
that the beneft from statin therapy is related to
both global risk and intensity of treatment,S4.3-12
and no RCTs of high-intensity statin therapy have
been carried out in cohorts of patients exclusively
with diabetes mellitus. On the basis of these con
siderations and the fact that patients with diabe
tes mellitus have a higher trajectory of lifetime risk
than do those without diabetes mellitus, high-
intensity statin therapy is preferred in patients
with diabetes mellitus as they age or develop risk
modifers (Table 5).
4. ASCVD risk increases incrementally with age in
diabetes mellitus.S4.3-5,S4.3-6,S4.3-8 In one long-term
cohort study of type 2 diabetes mellitus with
out ASCVD, incident rates of MI averaged 25.6
per 1000 person-yearsS4.3-5 in those >75 years of
age, while another in a type 1 diabetes mellitus
cohort found the 10-year fatal CVD risk in those
>75 years of age was 70% in men and 40% in
women.S4.3-8 Although no controlled statin tri
als in people >75 years of age are available, a
meta-analysis of the JUPITER (Justifcation for
the Use of Statins in Prevention: an Intervention
Trial Evaluating Rosuvastatin) and HOPE-3 (Heart
Outcomes Prevention Evaluation) trials dem
onstrated similar benefts in ASCVD reduc
tion among those >70 of age versus <70 years
of age.S4.3-26 Although that study included few
patients with diabetes mellitus, it does support
the continuation of moderate- or high-intensity
statin therapy for primary prevention in those >75
years of age with diabetes mellitus, who comprise
21% of the population in this age category. The
clinician should note that the beneft may be off
set by limited life span or increased susceptibility
to adverse events in patients in this age group.

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5. According to a CTT analysis,S4.3-12 the higher
the 10-year ASCVD risk, the greater is the ben
eft from increased LDL-C reduction. This is
supported by the meta-analyses comparing high-
intensity versus -low-intensity statin therapyS4.3-12
and those comparing the beneft of statins and
nonstatin therapeutic agents (ie, ezetimibe, bile
sequestrants, PCSK9 antagonists) that upregu
late LDL receptors.S4.3-27 Therefore, a risk discus
sion may be held on the benefts of achieving
>=50% LDL-C lowering in adults with diabetes
mellitus who have >=20% ASCVD risk. Addition
of ezetimibe 10 mg/d to moderate-intensity statin
therapy can achieve the same percent LDL-C low
ering as that achieved with high-intensity statin
therapy.S4.3-14 In this RCT, 27% of patients had
diabetes mellitus.S4.3-28 Thus, ezetimibe added to
a moderate-intensity statin can be considered if a
high-intensity statin cannot be tolerated or does
not lower LDL-C, as expected, by >=50%.
6. Although the risk of ASCVD is high in adults >75
years of age with diabetes mellitusS4.3-5,S4.3-6,S4.3-8
who are not receiving statin therapy, particularly
those with additional risk factors or risk modif
ers, the beneft of initiating statin therapy in these
individuals may be limited by their reduced life
span or increased susceptibility to adverse effects
of treatment. Among this group will also be indi
viduals with recent or newly diagnosed diabetes
mellitus for whom the impact of diabetes mellitus
on ASCVD risk is not well known. It may there
fore be reasonable to have a clinician-patient dis
cussion in which the potential benefts and risks
of initiating statin therapy in this age group are
reviewed.
7. There is limited information on ASCVD rates
among individuals 20 to 39 years of age with
diabetes mellitus and no information on whether
statin therapy is benefcial in these individuals.
Available evidence indicates that although rates
of ASCVD are low in those <30 years of age,
they increase with timeS4.3-6,S4.3-17,S4.3-20,S4.3-23 and
may reach intermediate-risk levels by 30 to 39
years of age, especially in individuals with long
standing type 2 diabetes mellitus,S4.3-17 who may
have more advanced subclinical coronary athero
sclerosis than do nondiabetic subjects,S4.3-21 and in
those with type 1 diabetes mellitus of >20 years'
duration.S4.3-23 ASCVD rates will also be infu
enced by hypertension and diabetic microvascu
lar complications that may be prevalent in these
age groups.S4.3-18,S4.3-23 Thus, it may be reasonable
to have a discussion about initiating moderate-
intensity statin therapy with patients who have
had type 2 diabetes mellitus for at least 10 years
or type 1 diabetes mellitus for at least 20 years
and with patients with 1 or more major CVD
risk factors or complications, such as diabetic
retinopathy,S4.3-19 neuropathy,S4.3-16 nephropathy
(eGFR <60 mL/min/1.73 m2 or albuminuria >=30
mcg albumin/mg creatinine),S4.3-25 or an ABI of
<0.9S4.3-22,S4.3-24 (Table 5).
4.4. Primary Prevention
Primary prevention of ASCVD over the life span requires
attention to prevention or management of ASCVD risk
factors beginning early in life (Figure 2). One major AS
CVD risk factor is elevated serum cholesterol, usually
identifed clinically as measured LDL-C. Screening can
be performed with fasting or nonfasting measurement
of lipids. In children, adolescents (10 to 19 years of age),
and young adults (20 to 39 years of age), priority should
be given to estimation of lifetime risk and promotion of
lifestyle risk reduction. Drug therapy is needed only in se
lected patients with moderately high LDL-C levels (>=160
mg/dL [>=4.1 mmol/L]) or patients with very high LDL-C
levels (190 mg/dL [4.9 mmol/L]). Three major higher-risk
categories are patients with severe hypercholesterol
emia (LDL-C levels >=190 mg/dL [>=4.9 mmol/L]), adults
with diabetes mellitus, and adults 40 to 75 years of age.
Patients with severe hypercholesterolemia and adults 40
to 75 years of age with diabetes mellitus are candidates
for immediate statin therapy without further risk assess
ment. Adults with diabetes mellitus should start with a
moderate-intensity statin, and as they accrue multiple
risk factors, a high-intensity statin may be indicated. In
other adults 40 to 75 years of age, 10-year ASCVD risk
should guide therapeutic considerations. The higher the
estimated ASCVD risk, the more likely the patient is to
beneft from evidence-based statin treatment. The risk
discussion should also consider several "risk enhancers"
that can be used to favor initiation or intensifcation of
statin therapy. When risk is uncertain or if statin ther
apy is problematic, it can be helpful to measure CAC
to refne risk assessment. A CAC score predicts ASCVD
events in a graded fashion and is independent of other
risk factors, such as age, sex, and ethnicity.S4.4-1 A CAC
score equal to zero is useful for reclassifying patients to
a lower-risk group, often allowing statin therapy to be
withheld or postponed unless higher risk conditions are
present. For patients >75 years of age, RCT evidence
for statin therapy is not strong, so clinical assessment of
risk status in a clinician-patient risk discussion is need
ed for deciding whether to continue or initiate statin
treatment.S4.4-2-S4.4-21
4.4.1. Evaluation and Risk Assessment
4.4.1.1. Essential Process of Risk Assessment
Children and adolescents should be tested for lipid dis
orders as described in Section 4.4.4.3. Risk assessment
in young adults 20 to 39 years of age is discussed in
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Figure 2. Primary prevention.
Colors correspond to Class of Recommendation in Table 2. apoB indicates apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery
calcium; HIV, human immunodefciency virus; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; and Lp(a), lipoprotein (a).
Section 4.4.4.2. In the young adult age group, mea
surement of risk factors allows for estimation of life
time risk of ASCVD. (See the risk calculators provided
on the ACC and AHA websites.S4.4.1.1-1,S4.4.1-2) Young
adults with moderate hypercholesterolemia (LDL-C
levels 160-189 mg/dL [4.1-4.8 mmol/L]) may be can
didates for cholesterol-lowering drugs. After age 20
years, traditional risk factors should be assessed every
4 to 6 years.S4.4.1.1-3,S4.4.1.1-4
In adults who are free from ASCVD, traditional
ASCVD risk factors should be assessed every 4 to 6
years.S4.4.1.1-3,S4.4.1.1-4 Adults 40 to 75 years of age are po
tential candidates for statin therapy. Selection of pa
tients for statin therapy is a multistep process. The frst
step to determine individual risk of clinical ASCVD is
to categorize patients into 4 categories of risk, from
high to low. The categories with highest overall risk
(secondary prevention and primary LDL-C levels >=190
mg/dL [>=4.9 mmol/L]) require prompt treatment to
lower ASCVD risk without using risk calculation by the
PCE, which were introduced in 2013. Adults 40 to 75
years of age with diabetes mellitus merit initiation of a
moderate-intensity statin without using risk calculation
by the PCE; however, it is reasonable to use PCE to fur
ther stratify risk (Section 4.3. on diabetes mellitus). The
fourth category includes adults 40 to 75 years of age
whose 10-year ASCVD risk is estimated by the PCE. This
leads to the clinician-patient risk discussion to consider
the pros and cons of statin therapy; factors to consider
are PCE scoring, presence or absence of other risk-en
hancing factors, potential beneft of intensifed lifestyle
therapy, likelihood of statin-associated side effects or
drug-drug interactions, and patient choice. If risk sta
tus remains uncertain after these considerations, mea
surement of CAC can provide additional information to
help make a decision with regard to statin therapy.
4.4.1.2. Pooled Cohort Equations
Several algorithms have been proposed for estimation
of 10-year risk.S4.4.1.2-1-S4.4.1.2-6 A useful one, and the most
representative algorithm for the United States, is one
derived from 5 prospective community-based studies
representing a broad spectrum of the US population

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(PCE)S.4.4.1.2-4,S.4.4.1.2-5 and validated in a similar natural his
tory study.S4.4.1.2-7 The PCE estimate risk of hard ASCVD
events (MI and stroke, both fatal and nonfatal). Esti
mates are readily applied in clinical practice. Their risk
factors include age, cigarette smoking, blood pressure,
serum TC, HDL-C, and presence or absence of diabetes
mellitus. The race and sex-specifc PCE are best validat
ed in non-Hispanic blacks and non-Hispanic whites 40
to 75 years of age.S4.4.1.2-1-S4.4.1,2-3,S4.4.1.2-7-S4.4.1.2-19 In other
racial/ethnic groups, equations are less extensively stud
ied. Because the PCE are population equations, they
may overestimate or underestimate risk for individu
als or population subgroups. Consequently, PCE esti
mates must be considered in the context of a particu
lar patient's circumstances when deciding whether to
use statin therapy. Using the PCE, the 2013 ACC/AHA
guidelinesS4.4.1.2-5 identifed a 10-year risk of ASCVD
>=7.5% as an RCT-supported threshold for beneft of
statin therapy. In this guideline, 10-year risk for ASCVD
is categorized as low-risk (<5%), borderline risk (5% to
<7.5%), intermediate risk (7.5% to <20%), and high
risk (>=20%). In adults 20 to 39 years of age, assess
ment of 30-year or lifetime risk of a frst ASCVD event
can be used to inform intensity of primary-prevention
efforts.S4.4.1.2-20,S4.4.1.2-21 PCE estimates can be calculated
from 2 online links: ACCS4.4.1.1-1 or AHA.S4.4.1.1-2
4.4.1.3. Risk-Enhancing Factors
Moderate intensity generic statins allow for effcacious
and cost-effective primary prevention in patients with a
10-year risk of ASCVD >=7.5%.S4.4.1.3-1 Since 2013 ACC/
AHA guidelines,S4.4.1.3-2 the HOPE-3 RCTS4.4.1.3-3 provided
additional support for this fnding. The pooled cohort
equation (PCE) is the single most robust tool for esti
mating 10-year risk in US adults 40 to 75 years of age.
Its strength can be explained by inclusion of major, in
dependent risk factors. One limitation on the PCE when
applied to individuals is that age counts as a risk factor
and dominates risk scoring with advancing age. Age is
a powerful population risk factor but does not neces
sarily refect individual risk. Another factor infuencing
risk are baseline characteristics of populations (baseline
risk). These characteristics include both genetic and ac
quired risk factors other than established major risk fac
tors. Variation in baseline risk accounts for difference in
risk in different ethnic groups. Absolute risk predictions
depend on the baseline risk of a population (eg, the US
population). These considerations in patients at inter
mediate risk leave room in the clinician-patient risk dis
cussion to withhold or delay initiation of statin therapy,
depending on age, pattern of risk factors, and patient
preferences and values.
In sum, the PCE is a powerful tool to predict
population risk, but it has limitations when applied
to individuals. One purpose of the clinician patient
risk discussion is to individualize risk status based
Table 6. Risk-Enhancing Factors for Clinician-Patient Risk Discussion
Risk-Enhancing Factors
Family history of premature ASCVD (males, age <55 y; females,
age <65 y)
Primary hypercholesterolemia (LDL-C, 160-189 mg/dL [4.1-4.8 mmol/L);
non-HDL-C 190-219 mg/dL [4.9-5.6 mmol/L])*
Metabolic syndrome (increased waist circumference, elevated
triglycerides [>150 mg/dL], elevated blood pressure, elevated glucose,
and low HDL-C [<40 mg/dL in men; <50 in women mg/dL] are factors;
tally of 3 makes the diagnosis)
Chronic kidney disease (eGFR 15-59 mL/min/1.73 m2 with or without
albuminuria; not treated with dialysis or kidney transplantation)
Chronic infammatory conditions such as psoriasis, RA, or HIV/AIDS
History of premature menopause (before age 40 y) and history of
pregnancy-associated conditions that increase later ASCVD risk such as
preeclampsia
High-risk race/ethnicities (eg, South Asian ancestry)
Lipid/biomarkers: Associated with increased ASCVD risk
Persistently* elevated, primary hypertriglyceridemia (>=175 mg/dL);
If measured:
1. Elevated high-sensitivity C-reactive protein (>=2.0 mg/L)
2. Elevated Lp(a): A relative indication for its measurement is family
history of premature ASCVD. An Lp(a) >=50 mg/dL or >=125 nmol/L
constitutes a risk-enhancing factor especially at higher levels of Lp(a).
3. Elevated apoB >=130 mg/dL: A relative indication for its
measurement would be triglyceride >=200 mg/dL. A level >=130 mg/
dL corresponds to an LDL-C >=160 mg/dL and constitutes a risk-
enhancing factor.
4. ABI <0.9
*Optimally, 3 determinations.
AIDS indicates acquired immunodefciency syndrome; ABI, ankle-brachial
index; apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease;
eGFR, estimated glomerular fltration rate; HDL-C, high-density lipoprotein
cholesterol; HIV, human immunodefciency virus; LDL-C, low-density
lipoprotein cholesterol; Lp(a), lipoprotein (a); and RA, rheumatoid arthritis.
on PCE as well as other factors that may inform risk
prediction. Among these other factors are the risk-
enhancing factors discussed in this guideline. These
risk-enhancing factors are listed in Table 6, and evi
dence base and strength of association with ASCVD
are shown in Table S6. In the general population,
they may or may not predict risk independently of
PCE. But in the clinician-patient risk discussion they
can be useful for identifying specifc factors that in
fuence risk. Their presence helps to confrm a higher
risk state and thereby supports a decision to initi
ate or intensify statin therapy. They are useful for
clarifying which atherogenic factors are present in a
particular patient. And in some patients, certain risk-
enhancing factors carry greater lifetime risk than de
noted by 10-year risk prediction in the PCE. Finally,
several risk-enhancing factors may be specifc targets
therapy beyond those of the PCE.
A few comments may illustrate the potential use
fulness of risk-enhancing factors in the patient discus
sion. LDL-C >=160 mg/dL (>=4.1 mmol/L), apoB >=130
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mg/dL (particularly when accompanied by persistently
elevated triglycerides), and elevated Lp(a) denote high
lifetime risk for ASCVD and favor initiation of statin
therapy. The presence of family history of ASCVD, pre
mature menopause, and patients of South Asian race
appear to convey a higher baseline risk and are stron
ger candidates for statin therapy. Conditions associated
with systemic infammation (chronic infammatory dis
orders, metabolic syndrome, chronic renal disease, and
elevated hsCRP) appear to predispose to atherothrom
botic events, which reasonably justifes statin therapy in
intermediate-risk patients.
4.4.1.4. Coronary Artery Calcium
Substantial advances in estimation of risk with CAC
scoring have been made in the past 5 years. One pur
pose of CAC scoring is to reclassify risk identifcation
of patients who will potentially beneft from statin
therapy. This is especially useful when the clinician
and patient are uncertain whether to start a statin.
Indeed, the most important recent observation has been
the fnding that a CAC score of zero indicates a low
ASCVD risk for the subsequent 10 years.S4.4.1.4-1-S4.4.1.4-8
Thus, measurement of CAC potentially allows a cli
nician to withhold statin therapy in patients show
ing zero CAC. There are exceptions. For example,
CAC scores of zero in persistent cigarette smokers,
patients with diabetes mellitus, those with a strong
family history of ASCVD, and possibly chronic infam
matory conditions such as HIV, may still be associated
with substantial 10-year risk.S4.4.1.4-9-S4.4.1.4-12 Neverthe
less, a sizable portion of middle-aged and older pa
tients have zero CAC, which may allow withholding of
statin therapy in those intermediate risk patients who
would otherwise have a high enough risk according
to the PCE to receive statin therapy (Figure 2). Most
patients with CAC scores >=100 Agatston units have
a 10-year risk of ASCVD >=7.5%, a widely accepted
threshold for initiation of statin therapy.S4.4.1.4-13 With
increasing age, 10-year risk accompanying CAC scores
of 1 to 99 rises, usually crossing the 7.5% threshold in
later middle age.S4.4.1.4-13 When the CAC score is zero,
some investigators favor remeasurement of CAC af
ter 5 to 10 years.S4.4.1.4-14-S4.4.1.4-16 CAC measurement
has no utility in patients already treated with statins.
Statins are associated with slower progression of over
all coronary atherosclerosis volume and reduction of
high-risk plaque features, yet statins increase the CAC
score.S4.4.1.4-17 A prospective randomized study of CAC
scoring showed improved risk factor modifcation
without an increase in downstream medical testing or
cost.S4.4.1.4-18 In MESA (Multi-Ethnic Study of Athero
sclerosis), CAC scanning delivered 0.74 to l.27 mSv
of radiation, which is similar to the dose of a clinical
mammogram.S4.4.1.4-19 CAC scans should be ordered by
a clinician who is fully versed in the pros and cons of
diagnostic radiology.
4.4.2. Primary Prevention Adults 40 to 75 Years of
Age With LDL-C Levels 70 to 189 mg/dL (1.7 to 4.8
mmol/L)
Primary Prevention Recommendations for Adults 40 to 75 Years of
Age With LDL Levels 70 to 189 mg/dL (1.7 to 4.8 mmol/L)
Referenced studies that support recommendations are summarized
in Online Data Supplement 16.
COR
LOE
Recommendations
I
A
1. In adults at intermediate-risk, statin therapy
reduces risk of ASCVD, and in the context
of a risk discussion, if a decision is made for
statin therapy, a moderate-intensity statin
should be recommended.S4.4.2-1-S4.4.2-8
I
A
2. In intermediate-risk patients, LDL-C levels
should be reduced by 30% or more, and for
optimal ASCVD risk reduction, especially in
high-risk patients, levels should be reduced
by 50% or more.S4.4.2-1,S4.4.2-4-S4.4.2-9
I
B-NR
3. For the primary prevention of clinical
ASCVD* in adults 40 to 75 years of age
without diabetes mellitus and with an
LDL-C level of 70 to 189 mg/dL (1.7 to 4.8
mmol/L), the 10-year ASCVD risk of a frst
"hard" ASCVD event (fatal and nonfatal MI
or stroke) should be estimated by using the
race- and sex-specifc PCE, and adults should
be categorized as being at low risk (<5%),
borderline risk (5% to <7.5%), intermediate-
risk (>=7.5% to <20%), and high-risk
(>=20%).S4.4.2-10,S4.4.2-11
I
B-NR
4. Clinicians and patients should engage in a
risk discussion that considers risk factors,
adherence to healthy lifestyle, the potential
for ASCVD risk-reduction benefts, and
the potential for adverse effects and
drug-drug interactions, as well as patient
preferences, for an individualized treatment
decision.S4.4.2-12-S4.4.2-14
IIa
B-R
5. In intermediate-risk adults, risk-enhancing
factors favor initiation or intensifcation of
statin therapy.S4.4.2-6,S4.4.2-15-S4.4.2-22
IIa
B-NR
6. In intermediate-risk or selected
borderline-risk adults, if the decision about
statin use remains uncertain, it is reasonable
to use a CAC score in the decision to
withhold, postpone or initiate statin
therapy.S4.4.2-15,S4.4.2-17,S4.4.2-23
IIa
B-NR
7. In intermediate-risk adults or selected
borderline-risk adults in whom a CAC score
is measured for the purpose of making a
treatment decision, AND
 If the coronary calcium score is zero, it
is reasonable to withhold statin therapy
and reassess in 5 to 10 years, as long as
higher risk conditions are absent (diabetes
mellitus, family history of premature CHD,
cigarette smoking);
 If CAC score is 1 to 99, it is reasonable
to initiate statin therapy for patients >=55
years of age;
 If CAC score is 100 or higher or in the
75th percentile or higher, it is reasonable
to initiate statin therapy.S4.4.2-17,S4.4.2-23

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Primary Prevention Recommendations for Adults 40 to 75 Years
of Age With LDL Levels 70 to 189 mg/dL (1.7 to 4.8 mmol/L)
(Continued)
COR
LOE
Recommendations
IIb
B-R
8. In intermediate-risk adults who would
beneft from more aggressive LDL-C
lowering and in whom high-intensity
statins are advisable but not acceptable
or tolerated, it may be reasonable to
add a nonstatin drug (ezetimibe or bile
acid sequestrant) to a moderate-intensity
statin.S4.4.2-9
IIb
B-R
9. In patients at borderline risk, in risk
discussion, the presence of risk-enhancing
factors may justify initiation of moderate-
intensity statin therapy.S4.4.2-17,S4.4.2-24
*Defnition of clinical ASCVD includes acute coronary syndrome (ACS),
those with history of myocardial infarction (MI), stable or unstable angina or
coronary or other arterial revascularization, stroke, transient ischemic attack
(TIA), or peripheral artery disease (PAD) including aortic aneurysm, all of
atherosclerotic origin.
Synopsis
Adults 40 to 75 years of age in primary prevention can
be classifed as borderline risk (10-year risk of ASCVD
5% to <7.5%), intermediate-risk (7.5% to <20%),
and high-risk (20%). For intermediate-risk patients,
moderate- to high-intensity statin therapy should be
considered during risk discussion of treatment options.
Additional considerations favoring use of statins in in
termediate-risk patients include other independent risk
conditions and, in selected individuals, risk-enhancing
factors associated with greater ASCVD risk (Table 6).
Although the variability of percent LDL-C lowering
with high-intensity statin use is wide, its effcacy is
proportional to the magnitude of the LDL-C reduction
obtained.S4.4.2-18 Systematic reviews indicate that those
with higher baseline ASCVD risk derive greater absolute
beneft from higher percent LDL-C reduction with evi
dence-based therapy.S4.4.2-1,S4.4.2-7 Accordingly, if a statin
is given, LDL-C levels should be reduced by >=30% and
optimally by >=50%. When there is uncertainty, consid
eration of risk-enhancing factors including family his
tory of premature ASCVD and CAC score, categorical
risk factors, and selected biomarkers may inform the
decision. CAC scoring is especially useful in older adults
to improve specifcity.S4.4.2-15 A CAC score of zero revises
ASCVD risk downward and selects adults who show
reduced beneft from starting a statin.S4.4.2-20
Recommendation-Specifc Supportive
Text
1. Prior guidelines recommended moderate- or high-
intensity statins as frst-line LDL-C-lowering ther
apy in primary prevention of ASCVD after a risk
discussion of treatment options. This was based
on 3 large-scale exclusively primary-prevention
RCTs that demonstrated that moderate-intensity
statin therapyS4.4.2-5,S4.4.2-25 and high-intensity statin
therapyS4.4.2-6 were associated with ASCVD risk
reduction that outweighed the observable risks.
Since those ACC/AHA 2013 guidelines, a large-
scale RCT in a racially/ethnically diverse population
confrmed statin beneft from a moderate-inten
sity dose of a statin as compared with placebo in
intermediate-risk patients. That RCT enrolled men
>=55 years of age and women >=65 years of age
with at least 1 cardiovascular risk factor. In the
placebo group, the 10-year risk of "hard" ASCVD
was 8.7%, and the risk of the expanded ASCVD
endpoint that included coronary revascularization
was 10%.S4.4.2-8 After 5.6 years, those assigned
to rosuvastatin 10 mg/d demonstrated signif
cant ARR in both co-primary endpoints with an
acceptable safety record. By comparison, after a
median follow-up of 1.9 years, those assigned a
high-intensity dose of rosuvastatin in the JUPITER
RCT achieved greater LDL-C-lowering and greater
reductions in ASCVD outcomes. This corroborates
meta-analyses demonstrating increased net ben
eft of evidence-based LDL-C-lowering therapy
in those at risk if greater reductions in LDL-C are
attained.S4.4.2-1,S4.4.2-9
2. If in the context of a risk discussion, maximal
ASCVD risk reduction is desired, it is reasonable
to use a high-intensity statin to lower LDL-C by
>=50%. This provides increased beneft, espe
cially when 10-year ASCVD risk is >=20%. JUPITER
enrolled men >=50 years of age and women 60
years of age with high-sensitivity C-reactive
protein values 2.0 mg/L. Participants randomly
assigned to 20 mg/d of rosuvastatin achieved
median reductions in LDL-C of 50% and highly
signifcant ASCVD risk reduction at 1.9 years.S4.4.2-6
The trial was stopped prematurely because of
a highly signifcant reduction in cardiovascular
death. However, wide individual variability in per
cent LDL-C reduction was noted. Importantly, the
magnitude of the percent LDL-C reduction deter
mined beneft.S4.4.2-18 The US Preventive Services
Task Force systematic review of statin therapy
in primary prevention showed a reduced risk of
all-cause and cardiovascular death and ASCVD
events and noted greater absolute benefts in
those at greater baseline risk,S4.4.2-4 consistent
with other high-quality systematic reviews and
meta-analyses.S4.4.2-1,S4.4.2-7,S4.4.2-24 This underscores
the need for aggressive and safe risk reduction in
the highest-risk groups and the need for follow
up LDL-C testing to determine adherence and
adequacy of effect of the prescribed statin.S4.4.2-26
3. In individuals 40 to 75 years of age, 10-year ASCVD
risk assessment begins the clinician-patient risk
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discussion.S4.4.2-13,S4.4.2-26 Required information
includes age, sex, and race/ethnicity; presence of
diabetes mellitus or cigarette smoking and treated
hypertension; and a current blood pressure level
and fasting or nonfasting TC and HDL-C levels.
The PCE include a stroke endpoint and race-
specifc coeffcients. This identifes, for example,
a black woman who with similar risk factors is
at much higher risk than her white counterpart.
The PCE were externally validated in a high-qual
ity natural history study published shortly after
the 2013 ACC/AHA cholesterol guidelines were
presented.S4.4.2-11 These equations may underesti
mate risk in individuals of South Asian ancestry
and other high-risk groups and may overestimate
risk in selected lower-risk groups.S4.4.2-10 Unlike
other risk estimators, the PCE use only fatal and
nonfatal stroke and CHD as endpoints. Other
risk estimators that include revascularization and
additional cardiovascular endpoints provide risk
estimates that cannot be compared directly with
those given by the PCE. Finally, the potential for
errors in estimating ASCVD risk at both ends of
the risk curve (low risk and high-risk) as noted
for individuals can be reviewed in the clinician-
patient risk discussion (Table 6).
4. The present guidelines continue to empha
size the importance of a clinician-patient risk
discussion.S4.4.2-12-S4.4.2-14,S4.4.2-27,S4.4.2-28
In
those
with a 10-year ASCVD risk of >=7.5%, it is rec
ommended that the discussion occur before a
statin prescription is written.S4.4.2-26 This frank
discussion, as recommended in the 2013 ACC/
AHA cholesterol guidelines,S4.4.2-26 should con
sider whether ASCVD risk factors have been
addressed, evaluate whether an optimal life
style has been implemented, and review the
potential for statin beneft versus the potential
for adverse effects and drug-drug interactions.
Then, on the basis of individual characteristics
and including an informed patient preference
in shared decision-making, a risk decision about
statin therapy can be made (Table 7). Clinicians
should indicate that as ASCVD risk increases, so
does beneft of evidence-based LDL-C-lower
ing therapy. They may wish to review the drug
and safety sections of the present guideline
and stay informed on safety information that is
essential for a balanced discussion. Importantly,
for those at intermediate-risk, especially those
>55 years of age, risk-enhancing factors or CAC
can be used to clarify risk if the risk decision is
uncertain.S4.4.2-16 Risk-enhancing factors, such as
family history of premature ASCVD or an LDL-C
of 160 to 189 mg/dL (4.1-4.8 mmol/L), identify
Table 7. Checklist for Clinician-Patient Shared Decision-Making for
Initiating Therapy
Checklist Item
Recommendation
ASCVD risk
Assign to statin treatment group; use ASCVD Risk
assessment
Estimator Plus.*
In lower-risk primary-prevention adults 40-75 y of
age with LDL-C >=70 mg/dL (>=1.8 mmol/L).
Not needed in secondary prevention, in those
with LDL-C >=190 mg/dL (>=4.9 mmol/L), or in
those 40-75 y of age with diabetes mellitus.
Assess other patient characteristics that infuence
risk. See Risk-Enhancing Factors (Section 4.4.1.3.
and Table 6).
Assess CAC (Section 4.4.1.4.) if risk decision is
uncertain and additional information is needed to
clarify ASCVD risk.
Use decision tools to explain risk (eg, ASCVD
Risk Estimator Plus,* Mayo Clinic Statin Choice
Decision Aid).
Lifestyle
Review lifestyle habits (eg, diet, physical activity,
modifcations
weight or body mass index, and tobacco use).
Endorse a healthy lifestyle and provide relevant
advice, materials, or referrals (eg, CardioSmart,
AHA Life's Simple 7, NLA Patient Tear Sheets,
PCNA Heart Healthy Toolbox, cardiac
rehabilitation, dietitian, smoking cessation
program).
Potential net
Recommend statins as frst-line therapy.
clinical beneft of
Consider the combination of statin and nonstatin
pharmacotherapy
therapy in selected patients.
Discuss potential risk reduction from lipid-lowering
therapy.
Discuss the potential for adverse effects or drug-
drug interactions.
Cost considerations
Discuss potential out-of-pocket cost of therapy to
the patient (eg, insurance plan coverage, tier level,
copayment).
Shared decision-
Encourage the patient to verbalize what was
making
heard (eg, patient's personal ASCVD risk, available
options, and risks/benefts).
Invite the patient to ask questions, express values
and preferences, and state ability to adhere to
lifestyle changes and medications.
Refer patients to trustworthy materials to aid
in their understanding of issues regarding risk
decisions.
Collaborate with the patient to determine therapy
and follow-up plan.
*ASCVD Risk Predictor Plus is available at: http://tools.acc.org/ASCVD-Risk
Estimator-Plus/#!/calculate/estimate/ and http://static.heart.org/riskcalc/app/
index.html#!/baseline-risk. Accessed September 1, 2018.
Mayo Clinic Statin Decision Aid information is available at: https://
statindecisionaid.mayoclinic.org.
CardioSmart health information is available at: https://www.cardiosmart.
org/About.
AHA Life's Simple 7 information is available at: https://www.heart.org/en/
healthy-living/healthy-lifestyle/my-life-check-lifes-simple-7.
NLA Patient Tear Sheets information is available at: https://www.lipid.org/
practicetools/tools/tearsheets.
PCNA Heart Healthy Toolbox information is available at: http://pcna.net/
clinical-tools/tools-for-healthcare-providers/heart-healthy-toolbox.
AHA indicates American Heart Association; ASCVD, atherosclerotic
cardiovascular disease; CAC, coronary artery calcium; CKD, chronic kidney
disease; HIV, human immunodefciency virus; LDL-C, low-density lipoprotein
cholesterol; PCNA, Preventive Cardiology Nurses Association and NLA,
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individuals whose ASCVD risk may indicate risk
of genetic hypercholesterolemia and hence who
may beneft from a moderate- to high-intensity
statinS4.4.2-21 (Table 6).
5. In those with intermediate ASCVD risk, defned
as an ASCVD risk of 7.5% to <=20%, knowledge
of risk-enhancing factors is useful in understand
ing patient characteristics that increase ASCVD
risk both short and long-term (Table 6). As in the
2013 ACC/AHA guideline, an ASCVD score does
not assign a statin; it begins the decision process,
which includes consideration of risk-enhancing
factors. For example, in an RCT,S4.4.2-9 a family
history of premature ASCVD identifed women
>=60 years of age with elevated high-sensitivity
C-reactive protein but without ASCVD who ben
eftted from high-intensity statin therapy. Those
with primary elevations of LDL-C >=160 mg/dL (4.1
mmol/L) have elevated lifetime ASCVD risk and
beneft from statin therapy.S4.4.2-21,S4.4.2-22,S4.4.2-25,
S4.4.2-29,S4.4.2-30 Increased ASCVD riskS4.4.2-2 is seen
with metabolic syndrome;S4.4.2-20 infammatory
diseases, including psoriasisS4.4.2-31 and RA; and
HIV when treated with protease inhibitors.S4.4.2-32
In women, a history of pregnancy complicated
by preeclampsia or premature menopause (age
<40 years) also enhances ASCVD risk (see Section
4.4.5.3.). If measured, ABI <0.9 has been shown
to reclassify risk by the 2013 Risk Assessment
Guidelines.S4.4.2-33 The presence of risk-enhancing
factors may affect the threshold for statin initia
tion or intensifcation (see Sections 4.4.2, 4.4.4,
and 4.5). Finally, in selected individuals, biomark
ers, if measured, may identify individuals with
increased risk of ASCVD events. Lp(a) levels,
especially in those with a family history of prema
ture ASCVD, can increase risk.S4.4.2-16 However, no
available RCT evidence supports Lp(a) levels as a
target of therapy. Moderate primary elevations of
triglycerides, non-HDL-C (TC minus HDL-C), and,
if measured, apolipoprotein B (apoB) can improve
selection of those at increased ASCVD risk.S4.4.2-22
6. Evidence shows that a CAC score of zero can
"down-risk" individuals who otherwise would
qualify for a statin on the basis of their ASCVD
10-year risk. The ability to select those who would
beneft greatly from statin therapy, as shown by
RCTs in primary-prevention populationsS4.4.2-6,S4.4.2-8
and yet to withhold statin therapy in those least
likely to beneft would improve specifcity.S4.4.2-34
For example, a CAC score of zero in an analysis
of pooled US population-based studies accurately
discriminated between lower and higher CHD risk
in older adults.S4.4.2-19,S4.4.2-27 The BioImage Study
in older adultsS4.4.2-15 and MESAS4.4.2-17 showed
improved detection of individuals not likely to
Table 8. Selected Examples of Candidates for CAC Measurement Who
Might Beneft From Knowing Their CAC Score Is Zero
CAC Measurement Candidates Who Might Beneft From Knowing Their
CAC Score Is Zero
Patients reluctant to initiate statin therapy who wish to understand their
risk and potential for beneft more precisely
Patients concerned about need to reinstitute statin therapy after
discontinuation for statin-associated symptoms
Older patients (men, 55-80 y of age; women, 60-80 y of age) with low
burden of risk factorsS4.4.2-25 who question whether they would beneft
from statin therapy
Middle-aged adults (40-55 y of age) with PCE-calculated 10-year risk
of ASCVD 5% to <7.5% with factors that increase their ASCVD risk,
although they are in a borderline risk group
Caveats: If patient is intermediate risk and if a risk decision is uncertain and
a CAC score is performed, it is reasonable to withhold statin therapy unless
higher risk conditions such as cigarette smoking, family history of premature
ASCVD, or diabetes mellitus are present, and to reassess CAC score in 5-10
years. Moreover, if CAC is recommended, it should be performed in facilities
that have current technology that delivers the lowest radiation possible.
ASCVD indicates atherosclerotic cardiovascular disease; CAC, coronary
artery calcium; LDL-C, low-density lipoprotein cholesterol; and PCE, pooled
cohort equations.
beneft from statins when the CAC score was
zero. Selected examples of candidates for CAC
scoring who might beneft from knowing their
CAC score is zero are listed in Table 8. Clinicians
should not down-risk patients who are persistent
cigarette smokers, have diabetes mellitus, or have
a strong family history of ASCVD, as well as pos
sibly those with chronic infammatory conditions
whose CAC of zero does not rule out risk from
noncalcifed plaque.S4.4.2-35
7. In adults at intermediate-risk (predicted 10-year
risk of 7.5% to <20%), substantial data indicate
how CAC measurement can be effective in mean
ingfully reclassifying risk in a large proportion of
individuals.S4.4.2-15,S4.4.2-17,S4.4.2-36-S4.4.2-49 In such inter
mediate-risk adults, those with a CAC score >=100
Agatston units or CAC >=75th percentile appear
to have ASCVD event rates suggesting that statin
therapy would be benefcial.S4.4.2-17,S4.4.2-23 Those
with a CAC of zero appear to have 10-year event
rates in a lower range that suggests statin therapy
may be of limited value for these patients, with
few exceptions including patients with diabetes
mellitus, persistent smoking, and family history or
premature ASCVD. Cigarette smoking remains a
strong risk factor even in the presence of CAC
score of zero.S4.4.2-50,S4.4.2-51 In asymptomatic dia
betes mellitus, a CAC score of zero is associated
with a favorable 5-year prognosis; but after 5
years, the risk of mortality increases signifcantly
for diabetic individuals even in the presence of a
baseline CAC score of zero.S4.4.2-52 In patients with
a family history of ASCVD, CAC score of zero may
impart less short-term beneft from statin therapy,
but considering a high lifetime risk, long-term
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beneft cannot be discounted.S4.4.2-53 The same
holds for CAC score of zero and a high 10 year
risk (eg, >=20%).S4.4.2-34 For those with CAC scores
of 1 to 99 Agatston units, 10-year ASCVD event
rates are 3.8%, 6.5%, and 8.3% for age groups
45 to 54, 55 to 64, and 65 to 74 years,S4.4.2-23 sug
gesting that CAC scores in this range favor statin
initiation only in adults >55 years of age and indi
cating that risk reclassifcation is modest for indi
viduals with CAC scores of 1 to 99. Therefore,
for patients with CAC scores of 1 to 99, it is
reasonable to repeat the risk discussion. If these
patients remain untreated, repeat CAC measure
ment in 5 to 10 years may have some value in
reassessing for CAC progression, but data are
limited.S4.4.2-12,S4.4.2-13 A systematic review and
meta-analysis suggests that knowledge that
a patient's CAC score is greater than zero is
benefcial.S4.4.2-38 Selected examples of candidates
for CAC scoring who might beneft from know
ing that their CAC score is zero are listed in Table
8. There is an increased likelihood that lifestyle
therapies and drug therapy will be started or con
tinued with signifcant, albeit modest, changes in
risk factor levels and predicted risk levels.
8. Clinicians may need to address reducing ASCVD
risk in higher-risk primary-prevention patients
who either do not wish to take a statin or can
not tolerate the recommended intensity of statin
therapy. In such patients, it may be reasonable to
use LDL-C-lowering drugs that have been proven
safe and effective in RCTs, either as monotherapy
or combined with a statin.S4.4.2-9 One alternative
is a cholesterol absorption inhibitor. An RCT in
adults >=40 years of age with advanced CKD and
without known CHD at baseline found that the
addition of ezetimibe to a moderate-intensity
statin lowered LDL-C 43 mg/dL (1.1 mmol/L)
at 1 year.S4.4.2-54 After a median 4.9 years, ezeti
mibe and simvastatin 40 mg per day resulted in
a 17% proportional reduction in major athero
sclerotic events compared with placebo.S4.4.2-2
Another alternative is a nonsystemic bile acid
sequestrant. Bile acid sequestrants used as mono-
therapy reduced CHD endpoints in a large pri
mary-prevention trial.S4.4.2-55 Bile acid sequestrants
can bind other drugs, so other medications must
be avoided for 1 hour before and at least 3 to
4 hours after administration. Adding psyllium
can minimize constipation and can reduce the
bile acid sequestrant dose.S4.4.2-56 These therapies
should be considered in the context of a risk dis
cussion that reviews potential for beneft along
with tolerability and safety issues.
9. Beneft from statin therapy is seen in lower-risk
individuals.S4.4.2-24 Consideration of enhancing
factors in selected younger individuals in this
lower risk range, will improve the ability to detect
younger patients who develop MI before age 50
years.S4.4.2-58,S4.4.2-59 Nonetheless, the challenge
among those in a lower ASCVD risk category is to
include those who would beneft yet avoid cast
ing too wide a net, to minimize treating those
who would derive little beneft from statin assign
ment. This risk group benefts greatly from a clini
cian-patient risk discussion. To arrive at a shared
risk decision, clinicians should assess the patient's
priorities for health care, perceived ASCVD risk,
and prior risk-reduction experiences and should
use best practices to communicate numerical
risk.S4.4.2-27 The presence of risk-enhancing fac
tors provides useful information about short term
ASCVD risk favoring initiation of statin therapy
(Table 6).S4.4.2-58 Although a CAC score can be use
ful in selected individuals, it will be positive less
often in this lower-risk group than in those with
higher levels of ASCVD risk and is not recom
mended routinely.S4.4.2-17
4.4.3. Monitoring in Response to LDL-C-Lowering
Therapy
Recommendation for Monitoring
Referenced studies that support the recommendation are
summarized in Online Data Supplement 17.
COR
LOE
Recommendation
I
A
1. Adherence to changes in lifestyle and effects
of LDL-C-lowering medication should
be assessed by measurement of fasting
lipids and appropriate safety indicators 4
to 12 weeks after statin initiation or dose
adjustment and every 3 to 12 months
thereafter based on need to assess
adherence or safety.S4.4.3-1-S4.4.3-3
Recommendation-Specifc Supportive
Text
1. Goals for LDL-C lowering in response to life
style therapies or a prescribed intensity of statin
therapy are defned by percentage responses.
Clinical effcacy is monitored by measurement of
percentage reductions in LDL-C relative to base
line levels. Baseline LDL-C can be estimated by
pretreatment measurements, chart reviews, or
measurement after a short interruption of drug
therapy. Some clinicians are reluctant to interrupt
therapy, although risk is low. Unless a baseline
level is established, it will be diffcult to evaluate
response to therapy. Good adherence to various
LDL-lowering diets will reduce LDL-C levels by
10% to >15%.S4.4.3-3 Moderate-intensity statins
can be expected to reduce LDL-C levels by another
30% to 49%, and high-intensity statins by >=50%

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(Table 3, Section 3.2.). The addition of ezetimibe
or bile acid sequestrants to statin therapy typically
provides an additional 15% to 25% reduction in
LDL-C. Much greater additive reductions occur by
adding a PCSK9 inhibitor to statin plus ezetimibe.
In clinical practice, lifestyle and statin therapy are
commonly introduced together. The maximum
percentage change will occur by 4 to 12 weeks
after starting a statin or combined therapy. At this
time, drug effcacy or initial adherence to therapy
can be evaluated. Periodic remeasurements will
make it possible to confrm adherence to therapy.
Because recommended intensities of drug thera
pies will vary in adolescents, young adults, adults
40 to 75 years of age, those with severe hyper
cholesterolemia, and those receiving therapy for
secondary prevention, the recommended LDL-C
levels to achieve will also vary.
4.4.4. Primary Prevention in Other Age Groups
4.4.4.1. Older Adults
Additional recommendations for adults >75 years of
age are included in Section 4.1. (Secondary ASCVD Pre
vention) and Section 4.3. (Diabetes Mellitus in Adults).
Recommendations for Older Adults
Referenced studies that support recommendations are summarized
in Online Data Supplements 18 and 19.
COR
LOE
Recommendations
IIb
B-R
1. In adults 75 years of age or older with an
LDL-C level of 70 to 189 mg/dL (1.7 to 4.8
mmol/L), initiating a moderate-intensity
statin may be reasonableS4.4.4.1-1-S4.4.4.1-8
IIb
B-R
2. In adults 75 years of age or older, it may
be reasonable to stop statin therapy when
functional decline (physical or cognitive),
multimorbidity, frailty, or reduced life-
expectancy limits the potential benefts of
statin therapy.S4.4.4.1-9
IIb
B-R
3. In adults 76 to 80 years of age with an
LDL-C level of 70 to 189 mg/dL (1.7 to 4.8
mmol/L), it may be reasonable to measure
CAC to reclassify those with a CAC score of
zero to avoid statin therapy.S4.4.4.1-10,S4.4.4.1-11
Synopsis
Mounting risk factors and subclinical disease are en
demic in the rapidly growing population of older adults.
Data from RCTS4.4.4.1-1-S4.4.4.1-4 and a related meta-analy
sisS4.4.4.1-5 support primary prevention with statin thera
py in older adults up to age 79 years, but some studies
do not.S4.4.4.1-12 Nonetheless, data in older subsets (>=80
years of age) remain sparse.S4.4.4.1-6-S4.4.4.1-8 Furthermore,
as adults grow older they are more susceptible to statin
related risks,S4.4.4.1-13-S4.4.4.1-15 including those that arise
from altered pharmacokinetics and pharmacodynam
ics, as well as the impact of side effects on health is
sues such as multimorbidity, polypharmacy, frailty, and
cognitive decline. In some patients, the aggregate risks
associated with statins may exceed their likely benefts.
Limited life spans may also undercut the minimum time
for likely statin benefts, especially the 4 to 5 years as
sociated with statins' stroke-reducing benefts.S4.4.4.1-15
Decisions to not initiate statins, or even to depre
scribe them, are reasonable in older adults when
aggregate risks outweigh potential for meaningful
beneft.S4.4.4.1-9,S4.4.4.1-16-S4.4.4.1-18 A shared decision-making
process between clinicians and patients that targets
individualized decisions is warranted, with regular reas
sessments over time. CAC determinationS4.4.4.1-10,S4.4.4.1-11
focuses statin therapy on those who beneft most. For
older adults with CAC scores of zero, the likelihood of
benefts from statin therapy does not outweigh the risks.
Recommendation-Specifc Supportive
Text
1. An RCT enrolling 5084 men and women 70 to
82 years of age showed no beneft from pravas
tatin 40 mg/d versus placebo in the primary-
prevention subgroup.S4.4.4.1-12 Another RCT using
pravastatin 40 mg per day versus usual care in
older adults showed no statin beneftS4.4.4.1-19
but there were important concerns about both
adherence in those assigned to pravastatin
and drop-in statin therapy in those assigned to
usual care.S4.4.4.1-1,S4.4.4.1-2,S4.4.4.1-4 A recent meta
analysisS4.4.4.1-3 combining data from JUPITER
and HOPE-3 in those >=70 years of age showed
a statistically signifcant 26% RRR for nonfa
tal MI, nonfatal stroke, or cardiovascular death.
A prospective cohort studyS4.4.4.1-5 comparing
healthy older patients (age >=70 years) who used
statins with those who did not showed signif
cantly lower risk of death but nonsignifcant car
diovascular event reduction in the statin group.
Other recent meta-analysesS4.4.4.1-6-S4.4.4.1-8 support
primary prevention for adults in their 70s. Thus,
clinician-patient discussion of risk versus beneft
remains particularly important with inconsistent
support and few data for adults >80 years of
age. Even a small increase in geriatric-specifc
adverse effects with statins could offset any car
diovascular beneft.S4.4.4.1-20 Statins may be indi
cated if, after a clinician-patient discussion, the
potential for beneft is thought to outweigh the
risks of adverse effects, drug-drug interactions,
and cost.
2. A counterpoint to the rationale for statin therapy
in primary prevention for adults of older ages is
the compelling rationale to discontinue therapy
in older adults with severe age-related man
agement complexities. Customary risks associ
ated with statins may be intensifed by age (eg,
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myalgias)S4.4.4.1-9 and distinctive risks may also
develop because of the broader age context (eg,
multimorbidity, polypharmacy, sarcopenia, falls,
frailty, and cognitive decline),S4.4.4.1-15 potentially
confounding effective statin therapy. Aggregate
risks increase with age and may become dis
proportionate to the extent that risks outweigh
potential for meaningful beneft. Deprescribing
statins becomes an important option to be
considered.S4.4.4.1-18 Related studies are evolv
ing, particularly in the palliative care domain.
One randomized trialS4.4.4.1-9 and several nonran
domized studies (albeit of relatively lower qual
ity) show feasibility and utility of deprescribing
in older adults with signifcant management
complexity.S4.4.4.1-16,S4.4.4.1-17 Nonetheless, these studies
also show that decisions about statins are not intui
tive because many frailer or more complex patients
may prefer to stay on statins precisely because they
are at greatest cardiovascular risk.S4.4.4.1-16 Therefore,
it is warranted that decisions about statin therapy
be individualized and derived from clinician-patient
discussions. Moreover, given the predictable fuc
tuations of health dynamics, such shared decisions
should be reconsidered regularly.
3. Multiple studies indicate the utility of CAC mea
surement in identifying the absence of atheroscle
rotic pathophysiology in older adultsS4.4.4.1-10,S4.4.4.1-11
Moreover, with reduced costs, the long-term con
sequences of using low-dose computed tomogra
phy for CAC screening are much less concerning
for older patients. If CAC score is zero, the patient
may be reclassifed to a lower-risk status to avoid
statin therapy.S4.4.4.1-11The BioImage study also
indicated that scanning for carotid plaque did
not down-classify as many individuals as did a
CAC score of zero but still improved specifcity of
statin assignment.S4.4.4.1-11 Limiting statin therapy
to those with CAC scores greater than zero, com
bined with clinical judgment and patient prefer
ence, could provide a valuable awareness with
which to inform shared decision-making.
4.4.4.2. Young Adults (20 to 39 Years of Age)
Much of atherosclerosis begins in young adulthood.S4.4.4.2-1
Progression of atherosclerosis thereafter becomes clini
cally manifest as ASCVD in middle age or later years.
Thus, prevention of clinical ASCVD optimally begins
early in life. In children or adolescents, atherosclerosis
may begin to appear in those with hypercholesterol
emia; in this age range, more aggressive cholesterol-
lowering may be indicated. Development of atheroscle
rosis in young adults most commonly is multifactorial
and occurs most rapidly in individuals with multiple risk
factors (eg, hypercholesterolemia, hypertension, ciga
rette smoking, diabetes mellitus, and obesity).S4.4.4.2-2
As discussed in these guidelines (Section 4.2.) FH of
ten goes undiagnosed. Young adults with primary el
evations of LDL-C >=190 mg/dl have a long-term ASCVD
burden,S4.4.4.2-3 and statin therapy is recommended. In
adults with hypercholesterolemia, cascade screening
often identifes other family members with elevated
LDL-C (Section 4.2.).
However even moderate hypercholesterolemia can
accelerate development of atherosclerosis.S4.4.4.2-4 Sec
ondary causes of elevated cholesterol-hypothyroidism
(TSH), obstructive liver disease (liver panel), renal disease
and nephrosis (creatinine and urine analysis) as well as
dietary and medication history-should be addressed
appropriately.S4.4.4.2-5 Elevations of LDL-C persisting af
ter excluding secondary causes suggests genetic forms
of hypercholesterolemia. Young adults who experience
prolonged exposure to hyperlipidemia prior to age 55
are shown to have signifcantly increased risk of coro
nary heart disease.S4.4.4.2-6 Intensive lifestyle change has
the potential to reduce the hyperlipidemia and associ
ated ASCVD risk factor burden.
A smaller group, but even at higher risk, are young
adults with persistent, moderate hypercholesterolemia
(LDL-C 160-189 mg/dL), especially when risk-enhanc
ing factors, such as a family history of premature AS
CVD, are present. Since there is increased probability of
genetic FH in this LDL-C range, clinical judgment would
suggest that these high risk young adults will beneft
from long-term statin therapyS4.4.4.2-7 (Section 4.2.). In
deed, it has been shown that those with higher LDL-C
can gain as much or more beneft from cholesterol re
duction as do those with lower pretreatment LDL-C but
at higher risk.S4.4.4.2-8,S4.4.4.2-9
In young adults without phenotypically severe hy
percholesterolemia, risk assessment should begin by
estimation of lifetime risk.S4.4.4.2-10 The pooled cohort
equations (PCE) can be used to estimate lifetime risk
starting at age 21 years (see Section 4.4.2.). This
information can inform a focused risk discussion
designed to improve high-risk lifestyle behaviors in
cluding tobacco use, sedentary lifestyle and/or poor
diet.S4.4.4.2-11,S4.4.4.2-12 When young adults with hyper
cholesterolemia or multiple risk factors are identifed,
lifestyle intervention is indicated. To date, no long
term RCTs with cholesterol-lowering drugs have been
carried out in those 20 to 39 years age. However, a
primary prevention RCT in those younger individuals
at low to moderate short-term risk, but at high lifetime
risk has been proposed.S4.4.4.2-13
One approach to identifying young adults who
could beneft from statins or drug combination would
be to detect signifcant coronary atherosclerosis with
coronary artery calcium (CAC) scores. Its use for this
purpose has been suggested.S4.4.4.2-14 But again, ab
sence of RCT data precludes guideline recommenda
tions at this time.

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CLINICAL STATEMENTS
AND GUIDELINES

4.4.4.3. Children and Adolescents
Recommendations for Children and Adolescents
Referenced studies that support recommendations are summarized
in Online Data Supplements 18 to 21.
COR
LOE
Recommendations
I
A
1. In children and adolescents with
lipid disorders related to obesity, it is
recommended to intensify lifestyle therapy,
including moderate caloric restriction and
regular aerobic physical activity.S4.4.4.3-1-S4.4.4.3-4
I
B-NR
2. In children and adolescents
with lipid abnormalities, lifestyle
counseling is benefcial for lowering
LDL-C.S4.4.4.3-1-S.4.4.4.3-3,S4.4.4.3-5-S4.4.4.3-12
IIa
B-R
3. In children and adolescents 10 years of age
or older with an LDL-C level persistently
190 mg/dL or higher (>=4.9 mmol/L) or
160 mg/dL or higher (4.1 mmol/L) with
a clinical presentation consistent with FH
(see Section 4.2.) and who do not respond
adequately with 3 to 6 months of lifestyle
therapy, it is reasonable to initiate statin
therapy.S4.4.4.3-13-S4.4.4.3-16
IIa
B-NR
4. In children and adolescents with
a family history of either early CVD* or
signifcant hypercholesterolemia, it is
reasonable to measure a fasting or nonfasting
lipoprotein profle as early as age 2 years
to detect FH or rare forms of
hypercholesterolemia.S4.4.4.3-17-S4.4.4.3-21
IIa
B-NR
5. In children and adolescents found to have
moderate or severe hypercholesterolemia,
it is reasonable to carry out reverse-cascade
screening of family members, which includes
cholesterol testing for frst-, second-, and
when possible, third-degree biological
relatives, for detection of familial forms of hy
percholesterolemia.S4.4.4.3-22-S4.4.4.3-24
IIa
C-LD
6. In children and adolescents with obesity or
other metabolic risk factors, it is reasonable
to measure a fasting lipid profle to detect
lipid disorders as components of the
metabolic syndrome.S4.4.4.3-25-S4.4.4.3-27
IIb
B-NR
7. In children and adolescents without
cardiovascular risk factors or family history of
early CVD, it may be reasonable to measure a
fasting lipid profle or nonfasting non HDL-C
once between the ages of 9 and 11 years,
and again between the ages of 17 and 21
years, to detect moderate to severe lipid
abnormalities.S4.4.4.3-19,S4.4.4.3-21,S4.4.4.3-27-S4.4.4.3-29
*Family history of early CVD is defned here as MI, documented angina, or
atherosclerosis by angiography in parents, siblings, grandparents, aunts, or
uncles (<55 years of age for men, <65 years of age for women).
TC >=240 mg/dL (>=6.2 mmol/L), LDL-C >=190 mg/dL (>=4.9
mmol/L), non-HDL-C >=220 mg/dL (>=5.7 mmol/L), or known primary
hypercholesterolemia.
Synopsis
Abnormal lipid levels are relatively common in chil
dren and adolescents, affecting approximately 1 in 5
adolescents.S4.4.4.3-25 Confrmed lipid disorders are less
common but occur frequently in the presence of obe
sity, often accompanied by cardiovascular risk factors,
and contribute to increased rates of cardiovascular and
metabolic morbidity and mortality. Severe hypercholes
terolemia (LDL >=190 mg/dL (>=4.9 mmol/L)) affects ~1 in
250 children and adolescents. Testing for lipid disorders
can identify both severe hypercholesterolemia and mul
tifactorial lifestyle-related dyslipidemia. Nonfasting lipid
testing is effective for initial screening purposes, and
non-HDL-C is a reasonable screening test. No available
evidence evaluates benefts of childhood lipid screen
ing for modifying CVD events or associated long-term
harm. However, signifcantly abnormal lipid levels track
from childhood to adulthood. Furthermore, subclinical
atherosclerosis, as measured by carotid intima-media
thickness, is abnormal in children with FH. Strong evi
dence shows that lifestyle modifcation improves lipid
levels in childhood without adverse effects on growth
and maturation; however, effect sizes are small, and
adherence may wane over time. Statins and nonstatins
lower TC and LDL-C with minimal adverse effects in
children and adolescents with severe hypercholesterol
emia. There are scant data on pharmacological treat
ment of multifactorial lifestyle-related dyslipidemia.
Recommendation-Specifc Supportive
Text
1. In children and adolescents with lipid abnor
malities and obesity, lifestyle-modifcation ther
apy should be intensifed over and above usual
therapy for childhood obesity and should include
moderate caloric restriction and suffcient physi
cal activity (eg, 30-60 minutes of moderate to
vigorous activity on most days). Utilization of
resources for nutritional education and counsel
ing is encouraged.
2. Lifestyle-modifcation interventions in childhood
and adolescence show short- and long-term
benefts to lipid levels and subclinical atheroscle
in RCTsS4.4.4.3-5-S4.4.4.3-8
rosis measures
and obser
vational studies of children and adolescents
with lipid disorders.S4.4.4.3-3,S4.4.4.3-9 No adverse
effects on growth or maturation have been
demonstrated.S4.4.4.3-6 The impact of these inter
ventions on lipid levels and subclinical atheroscle
rosis is small; no studies report CVD event rates.
There are likely other unmeasured health benefts
of lifestyle-modifcation interventions for chronic
disease outcomes (eg, obesity, diabetes mellitus,
and cancer). These benefts support the recom
mendation to treat children and adolescents with
lipid disorders with lifestyle-modifcation interven
tions, generally by using a family-based approach
and promoting a heart-healthy diet, plenty of
physical activity, avoidance of cigarette smoking,
maintenance of a healthy weight, maintenance of
normal blood pressure, and maintenance of nor
mal glycemia.
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3. Statins and nonstatins lower TC and LDL-C in chil
dren and adolescents with FH,S4.4.4.3-30 and other
health conditions that put them at increased
risk of CVD.S4.4.4.3-31,S4.4.4.3-32 Evidence from these
RCTs demonstrates low short- and medium-term
adverse event rates (abnormalities in liver func
tion test, creatine kinase [CK] levels, and reported
myopathy) with statin use in children and ado
lescents with FH.S4.4.4.3-30 Limited data show ben
eft from statins to subclinical atherosclerosis
in FH. These data, coupled with the increased
risk of CVD in untreated severe hypercholester
olemia, support the use of statins in children
and adolescents at ages >=10 years who have
FHS4.4.4.3-33,S4.4.4.3-34 and have not responded to 3
to 6 months of lifestyle therapy. Statins may be
considered at age 8 years in the presence of con
cerning family history, extremely elevated LDL-C
level, or elevated Lp(a), in the context of informed
shared decision-making and counseling with the
patient and family. The intensity of treatment
should be based on the severity of the hyper
cholesterolemia and should incorporate patient/
family preference. Scant data on the use of ezeti
mibe in children with severe hypercholesterolemia
show reasonable LDL-C lowering with no signif
cant adverse effects.S4.4.4.3-13 Nonsystemic bile acid
sequestrants can be useful for LDL-C lowering,
but tolerability is an issue.S4.4.4.3-13-S4.4.4.3-16
4. Lipid testing during childhood can identify the
severe hypercholesterolemia phenotype.S4.4.4.3-35
Severe hypercholesterolemia, which includes FH,
can be identifed in children and adolescents
with an LDL-C level >=190 mg/dL (>=4.9 mmol/L).
Moreover, children and adolescents with LDL-C
>=160 mg/dL (>=4.1 mmol/L) and a family history
of early atherosclerosis or similarly elevated cho
lesterol in 1 parent likely are those with FH and
related genetic disorders associated with accel
erated ASCVD.S4.4.4.3-17-S4.4.4.3-21 Subclinical ath
erosclerosis data suggest divergence between
affected and unaffected children and adolescents
beginning at age 10 years,S4.4.4.3-28 which sup
ports screening by this age, although this topic
is still considered controversial.S4.4.4.3-36 Screening
is advised beginning at age 2 years if a family his
tory is suggestive of either early CVD or signifcant
primary hypercholesterolemia. Identifcation of
a child with severe hypercholesterolemia should
prompt screening of extended family members
(eg, reverse-cascade screening), according to
studies outside the United States demonstrating
effcacy of this approach.S4.4.4.3-37 Screening for
severe hypercholesterolemia on the basis of fam
ily history includes an expanded group of family
members (eg, grandparents, aunts, and uncles) in
Table 9. Normal and Abnormal Lipid Values in Childhood*
Acceptable,
mg/dL
Borderline,
mg/dL
Abnormal,
mg/dL
TC
<170
(<4.3 mmol/L)
170-199
(4.3-5.1 mmol/L)
>=200
(>=5.1 mmol/L)
Triglycerides
(0-9 y)
<75
(<0.8 mmol/L)
75-99
(0.8-1.1 mmol/L)
>=100
(>=1.1 mmol/L)
Triglycerides
(10-19 y)
<90
(<1.0 mmol/L)
90-129
(1.0-1.5 mmol/L)
>=130
(>=1.4 mmol/L)
HDL-C
>45
(>1.2 mmol/L)
40-45
(1.0-1.2 mmol/L)
<40
(<1.0 mmol/L)
LDL-C
<110
(<2.8 mmol/L)
110-129
(2.8-3.3 mmol/L)
>=130
(>=3.4 mmol/L)
Non-HDL-C
<120
(<3.1 mmol/L)
120-144
(3.1-3.7 mmol/L)
>=145
(>=3.7 mmol/L)
Values given are in mg/dL. To convert to SI units, divide the results for TC,
LDL-C, HDL-C, and non-HDL-C by 38.6; for triglycerides, divide by 88.6.
*Values for plasma lipid and lipoprotein levels are from the NCEP Expert
Panel on Cholesterol Levels in Children. Non-HDL-C values from the Bogalusa
Heart Study are equivalent to the NCEP Pediatric Panel cutpoints for LDL-C.
The cutpoints for high and borderline high represent approximately the
95th and 75th percentiles, respectively. Low cutpoints for HDL-C represent
approximately the 10th percentile.
HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density
lipoprotein cholesterol; NCEP, National Cholesterol Education Program; SI, Systeme
international d'unites (International System of Units); and TC, total cholesterol.
addition to parents and siblings because siblings
of children are unlikely to have had cardiovascular
events or been identifed with signifcant choles
terol disorders.S4.4.4.3-38
5. One advantage of measuring lipids in children
and adolescents is to identify genetic abnormali
ties in lipid metabolism that may be present in
other family members. Regardless of the age at
which abnormalities are detected, reverse-cas
cade screening in families is highly effective for
the identifcation of family members at risk of
ASCVD.S4.4.4.3-22-S4.4.4.3-24
6. Observational studies of children and adolescents
show that obesity and other lifestyle-related
behaviors and metabolic syndrome risk fac
tors including lipid abnormalities,S4.4.4.3-25,S4.4.4.3-26
and with subclinical atherosclerosis into young
adulthood,S4.4.4.3-38,S4.4.4.3-39 occur at higher rates
than in lean and otherwise healthy children and
adolescents. Longitudinal cohort data show mod
erate tracking of cardiovascular risk factors from
childhood to adulthood in the general pediatric
population,S4.4.4.3-40 suggesting some persistence
of the underlying pathophysiology and potential
beneft of identifying lipid disorders in childhood.
7. Selective screening for lipid disorders on the basis
of family history (Recommendation 1) or lifestyle-
related factors (Recommendation 2) identifes only
a portion of childhood lipid abnormalitiesS4.4.4.3-19,
S4.4.4.3-21,S4.4.4.3-26 (Table 9). Therefore, concordant
with the 2011 National Heart, Lung, and Blood
Institute Expert Panel on Integrated Guidelines

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CLINICAL STATEMENTS
AND GUIDELINES

for Cardiovascular Health and Risk Reduction in
Children and Adolescents,S4.4.4.3-41 universal pedi
atric lipid screening has been advised in recent
pediatric guidelines,S4.4.4.3-42 specifcally focusing
on ages 9 to 11 years and then ages 17 to 21
years because TC and LDL-C levels decrease 10%
to 20% during puberty. However, the long-term
benefts and harms of universal screening have not
been tested in RCTs. Observational studies demon
strate that universal screening can identify severe
lipid abnormalities,S4.4.4.3-18,S4.4.4.3-19 and in scant data
universal screening is associated with changes in
family lifestyle behaviors. Nonfasting lipid parame
ters are similar to fasting ones, and screening with
a nonfasting non-HDL-C is a reasonable approach
to population screening in childhood. Although
research on this topic continues, universal screen
ing may be reasonable given the substantial ben
efts of identifying severe hypercholesterolemia
(see Section 4.2., "Severe Hypercholesterolemia"),
including FH, and possible benefts of lifestyle
counseling for multifactorial dyslipidemias.S4.4.4.3-3,
S4.4.4.3-5-S4.4.4.3-9,S4.4.4.3-25,S4.4.4.3-26,S4.4.4.3-38-S4.4.4.3-40
4.5. Other Populations at Risk
4.5.1. Ethnicity
Recommendation for Other Populations at Risk
Referenced studies that support the recommendation are
summarized in Online Data Supplements 24 to 30.
COR
LOE
Recommendation
IIa
B-NR
1. For clinical decision-making in adults of
different race/ethnicities, it is reasonable
for clinicians to review race/ethnic features
that can infuence ASCVD risk.S4.5.1-1 so as
to adjust choice of statin or intensity of
treatmentS4.5.1-1-S4.5.1-4
Synopsis
Race/ethnicity factors can infuence estimations of AS
CVD risk,S4.5.1-S4.5.1-4 intensity of treatmentS4.5.1-1-S4.5.1-4 or
even lipid drug use.S4.5.1-5,S4.5.1-6 Important examples in
clude the heightened risk of ASCVD in those who iden
tify as South Asians, the increased sensitivity to statins
in those who identify as East Asians, and the increased
prevalence of hypertension in blacks. An important is
sue in management of ASCVD risk in those who iden
tify as Hispanics/Latinos in the United States is the lack
Table 10. Racial/Ethnic Issues in Evaluation, Risk Decisions, and Treatment of ASCVD Risk
Racial/Ethnic Groupings
Asian
AmericansS4.5.1-4, S4.5.1-13*
Hispanic/Latino
AmericansS4.5.1-7-S4.5.1-11
Blacks/African
AmericansS4.5.1-14
Comments
Evaluation
ASCVD issues informed by
ASCVD issues informed by race/
Race/ethnicity and country
ASCVD risk
There is heterogeneity in risk
race/ethnicity
ethnicity ASCVD risk in people
of origin, together with
assessment in black
according to racial/ethnic
of South Asian and East Asian
socioeconomic status and
women shows
group and within racial/ethnic
origin varies by country of origin;
acculturation level, may explain
increased ASCVD risk
groups. Native American/
individuals from South Asia (see
risk factor burden more precisely
compared with their
Alaskan populations have high
below) have increased ASCVD risk.
(eg, ASCVD risk is higher among
otherwise similar
rates of risk factors for ASCVD
individuals from Puerto Rico
white counterparts
compared with non-Hispanic
than those from Mexico).
whites.S4.5.1-12
Lipid issues informed by
race/ethnicityS4.5.1-15,S4.5.1-16
Asian Americans have lower levels of
HDL-C than whites.
Hispanic/Latino women have
higher prevalence of low
HDL-C compared to Hispanic/
Latino men.
Blacks have higher
levels of HDL-C
and lower levels
of triglycerides
than non-Hispanic
whites or Mexican
Americans.
All ethnic groups appear
to be at greater risk for
dyslipidemia, but important
to identify those with more
sedentary behavior and less
favorable diet.
There is higher prevalence of LDL-C
among Asian Indians, Filipinos,
Japanese, and Vietnamese than
among whites. An increased
prevalence of high TG was seen in
all Asian American subgroups.
Metabolic issues
informed by race/
ethnicityS4.5.1-3, S4.5.1-17, S4.5.1-18
Increased MetS is seen with lower
waist circumference than in whites.
DM is disproportionately
present compared with
whites and blacks. There
is increased prevalence of
MetS and DM in Mexican
Americans compared with
whites and Puerto Ricans.
There is increased
DM and
hypertension.
There is increased prevalence
of DM. Features of MetS
vary by race/ethnicity. Waist
circumference, not weight,
should be used to determine
abdominal adiposity when
possible.
DM develops at a lower lean body
mass and at earlier ages.S4.5.1-19-S4.5.1-21
Majority of risk in South Asians is
explained by known risk factors,
especially those related to insulin
resistance.S4.5.1-13
Risk Decisions
PCES4.5.1-22-S4.5.1-25
No separate PCE is available;
use PCE for whites. PCE may
underestimate ASCVD risk in South
Asians. PCE may overestimate risk in
East Asians.S4.5.1-26
No separate PCE is available;
use PCE for non-Hispanic
whites. If African-American
ancestry is also present, then
use PCE for blacks.
Use PCE for
blacks.S4.5.1-10
Country-specifc race/
ethnicity, along with
socioeconomic status, may
affect estimation of risk by
PCE.
(Continued)
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Table 10. Continued
Racial/Ethnic Groupings
Asian
AmericansS4.5.1-4, S4.5.1-13*
Hispanic/Latino
AmericansS4.5.1-7-S4.5.1-11
Blacks/African
AmericansS4.5.1-14
Comments
CAC scoreS4.5.1-27-S4.5.1-30
In terms of CAC burden, South
Asian men were similar to non-
Hispanic white men, but higher
CAC when than blacks, Latinos, and
Chinese Americans. South Asian
women had similar CAC scores
to whites and other racial/ethnic
women, although CAC burden
higher in older age.S4.5.1-31
CAC predicts similarly in
whites and in those who
identify as Hispanic/Latino.
In MESA, CAC score
was highest in white
and Hispanic men,
with blacks having
signifcantly lower
prevalence and
severity of CAC.
Risk factor differences in
MESA between ethnicities
did not fully explain variability
in CAC. However, CAC
predicted ASCVD events over
and above traditional risk
factors in all ethnicities.S4.5.1-32
Treatment
Lifestyle counseling (use
principles of Mediterranean
and DASH diets)
Use lifestyle counseling to
recommend a hearthealthy diet
consistent with racial/ethnic
preferences to avoid weight gain
and address BP and lipids.
Use lifestyle counseling to
recommend a hearthealthy
diet consistent with racial/
ethnic preferences to avoid
weight gain and address BP
and lipids.
Use lifestyle
counseling to
recommend a
hearthealthy diet
consistent with racial/
ethnic preferences to
avoid weight gain and
address BP and lipids.
Asian and Hispanic/
Latino groups need to be
disaggregated because of
regional differences in lifestyle
preferences. Challenge is
to avoid increased sodium,
sugar, and calories as groups
acculturate.
Intensity of statin therapy
and response to LDL-
Clowering
Japanese patients may be sensitive
to statin dosing. In an open-label,
randomized primaryprevention
trial, Japanese participants had a
reduction in CVD events with low-
intensity doses of pravastatin as
compared with placebo.S4.5.1-33 In a
secondary-prevention trial, Japanese
participants with CAD beneftted
from a moderate-intensity dose of
pitavastatin.S4.5.1-34
No sensitivity to statin dosage
is seen, as compared with
non-Hispanic white or black
individuals.
No sensitivity to
statin dosage is seen,
as compared with
non-Hispanic white
individuals.
Using a lower statin intensity
in Japanese patients may
give results similar to those
seen with higher intensities in
non-Japanese patients.
Safety
Higher rosuvastatin plasma levels are
seen in Japanese, Chinese, Malay,
and Asian Indians as compared
with whites.S4.5.1-35-S4.5.1-37 FDA
recommends a lower starting dose
(5 mg of rosuvastatin in Asians vs.
10 mg in whites). Caution is urged
as dose is uptitrated
There are no specifc
safety issues with statins
related to Hispanic/Latino
ethnicity.S4.5.1-38
Baseline serum CK
values are higher
in blacks than in
whites.S4.5.1-39 The
95th percentile race/
ethnicity- specifc and
sexspecifc serum
CK normal levels are
available for assessing
changes in serum CK.
Clinicians should take
Asian race into account
when prescribing dose of
rosuvastatin (See package
insert). In adults of East Asian
descent, other statins should
be used preferentially over
simvastatin.S4.5.1-5
*The term Asian characterizes a diverse portion of the world's population. Individuals from Bangladesh, India, Nepal, Pakistan, and Sri Lanka make up most of
the South Asian group.S4.5.1-26 Individuals from Japan, Korea, and China make up most of the East Asian group.
The term Hispanics/Latinos in the United States characterizes a diverse population group. This includes white, black, and Native American races. Their ancestry
goes from Europe to America, including among these, individuals from the Caribbean, Mexico, Central and South America.
ASCVD indicates atherosclerotic cardiovascular disease; BP, blood pressure; CAC, coronary artery calcium; CAD, coronary artery disease; CK, creatine kinase;
CVD, cardiovascular disease; DASH, Dietary Approaches to Stop Hypertension; DM, type 2 diabetes mellitus; FDA, US Food and Drug Administration; HDL-C,
high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MESA, Multi-Ethnic Study of Atherosclerosis; MetS, metabolic syndrome; and PCE,
pooled cohort equations.
of specifcity of the term Hispanic/Latino. Race/ethnic-
4.5.2. Hypertriglyceridemia
ity and country of origin, together with socioeconomic
status and acculturation level, should be discussed and
may explain ASCVD risk factor burden more precisely
than the generic term Hispanic/Latino.S4.5.1-6-S4.5.1-11 In
addition, those who identify as Native American/Alas
kan natives have high rates of risk factors for ASCVD
compared to non-Hispanic whites. In many ways, the
increase in metabolic risk factors and propensity for dia
betes mellitus resembles the risk profles of those who
identify as Mexican-Americans.S4.5.1-12 Table 10 reviews
these and other racial/ethnic issues that may be useful
in clinical management.
Recommendations for Hypertriglyceridemia
Referenced studies that support recommendations are summarized
in Online Data Supplements 31 and 32.
COR
LOE
Recommendations
I
B-NR
1. In adults 20 years of age or older with
moderate hypertriglyceridemia (fasting or
nonfasting triglycerides 175 to 499 mg/dL [2.0
to 5.6 mmol/L]), clinicians should address and
treat lifestyle factors (obesity and metabolic
syndrome), secondary factors (diabetes mellitus,
chronic liver or kidney disease and/or nephrotic
syndrome, hypothyroidism), and medications
that increase triglycerides.S4.5.2-1

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CLINICAL STATEMENTS
AND GUIDELINES

Recommendations for Hypertriglyceridemia (Continued)
COR
LOE
Recommendations
IIa
B-R
2. In adults 40 to 75 years of age with
moderate or severe hypertriglyceridemia
and ASCVD risk of 7.5% or higher, it
is reasonable to reevaluate ASCVD risk
after lifestyle and secondary factors are
addressed and to consider a persistently
elevated triglyceride level as a factor favoring
initiation or intensifcation of statin therapy
(see Section 4.4.2.).S4.5.2-2-S4.5.2-6
IIa
B-R
3. In adults 40 to 75 years of age with severe
hypertriglyceridemia (fasting triglycerides
>=500 mg/dL [>=5.6 mmol/L]) and ASCVD risk
of 7.5% or higher, it is reasonable to address
reversible causes of high triglyceride and to
initiate statin therapy.S4.5.2-3-S4.5.2-5,S4.5.2-7,S4.5.2-8
IIa
B-NR
4. In adults with severe hypertriglyceridemia
(fasting triglycerides >=500 mg/dL [>=5.7
mmol/L]), and especially fasting triglycerides
>=1000 mg/dL (11.3 mmol/L)), it is reasonable
to identify and address other causes of
hypertriglyceridemia), and if triglycerides are
persistently elevated or increasing, to further
reduce triglycerides by implementation of
a very low-fat diet, avoidance of refned
carbohydrates and alcohol, consumption
of omega-3 fatty acids, and, if necessary
to prevent acute pancreatitis, fbrate
therapy.S4.5.2-7,S4.5.2-9
Synopsis
Two categories of hypertriglyceridemia consist of moder
ate hypertriglyceridemia (fasting or nonfasting triglycer
ides 175-499 mg/dL [2.0-5.6 mmol/L]) and severe hyper
triglyceridemia (fasting triglycerides >=500 mg/dL [>=5.6
mmol/L]). In the former, excess triglycerides are carried
in VLDL. In the latter, most patients have elevated VLDL
plus chylomicrons. VLDL are believed to be atherogenic,
similar to LDL. There are many causes of elevated VLDL,
and it is reasonable to reduce their levels to reduce risk
of ASCVD. With severe hypertriglyceridemia, elevations
of VLDL raise risk of ASCVD, but increases in chylomi
crons impart risk of acute pancreatitis. Therapies should
address excesses in both lipoproteins.
Recommendation-Specifc Supportive
Text
1. In patients with moderate hypertriglyceride
mia, it is reasonable to reduce both atherogenic
VLDL and associated risk factors by nonpharma
cological means where possible. This can best be
achieved by identifcation and treatment of the
multiple underlying causes of elevated triglyc
erides (eg, lifestyle causes, secondary disorders,
and triglyceride-raising drugs).S4.5.2-1 Triglyceride-
raising drugs include oral estrogens, tamoxifen,
raloxifene, retinoids, immunosuppressive drugs
(cyclosporine, sirolimus, tacrolimus), beta blockers,
interferon, atypical antipsychotic drugs, protease
inhibitors, thiazide diuretics, glucocorticoids, rosi
glitazone, bile acid sequestrants, L-asparaginase,
and cyclophosphamide.
2. Most patients with severe hypertriglyceride
mia have multiple ASCVD risk factors and are
at enhanced risk of developing atherosclerotic
disease.S4.5.2-3-S4.5.2-5,S4.5.2-9 This risk is conveyed
by atherogenic VLDL plus other factors, such as
obesity, metabolic syndrome, and hyperglycemia.
Although chylomicronemia per se may not be ath
erogenic, in most patients it associates with other
atherogenic factors.S4.5.2-10-S4.5.2-13 For this reason,
initiation of statin therapy is reasonable. We stress
that statins alone cannot prevent increasing levels
of triglycerides in the face of secondary causes
(see Recommendation 1) from triggering acute
hypertriglyceridemic pancreatitis. Indeed, in the
pregnant woman with severe hypertriglyceride
mia, statins are not part of the treatment regimen
because they are not recommended at the pres
ent time in pregnancy. (See Section 5., "Statin
Safety and Statin-Associated Side Effects.")
3. Epidemiological studies show that patients with
moderate hypertriglyceridemia generally are at
increased risk of ASCVD.S4.5.2-2-S4.5.2-4 Few studies
that primarily recruited patients with hypertriglyceri
demia have been carried out with triglyceride-low
ering drugs. Statin therapy reduces VLDL similarly to
fbrates,S4.5.2-5 and statin trials include hypertriglyc
eridemic patients. Indeed, there is evidence to show
that VLDL excess increases the patient's ASCVD
risk and hence beneft from statin therapy.S4.5.2-6
Therefore, if an adult patient with moderate hyper
triglyceridemia has poorly controlled major risk fac
tors for ASCVD and a 10-year risk of ASCVD >=7.5%
by the PCE, it is reasonable to either initiate or inten
sify statin therapy. (See Section 4.4.2., "Primary
Prevention in Adults 40 to 75 Years of Age.")
4. Most patients with triglycerides >=500 mg/dL (>=5.6
mmol/L) have elevations of both VLDL and chylo
microns. Elevations of chylomicrons typically are
present when triglycerides are >=500 mg/dL (>=5.6
mmol/L), and chylomicronemia may cause acute
pancreatitis. The higher the triglyceride level, the
greater is the risk.S4.5.2-7 Patients with triglycerides
in the 500- to 999-mg/dL (5.6- to 11.2-mmol/L)
range are at risk of developing unrecognized
marked increases in triglycerides, leading to pan
creatitis. Most cases of severe hypertriglyceridemia
have a genetic component, but secondary factors
may contribute.S4.5.2-9,S4.5.2-14 To prevent acute pan
creatitis, it is reasonable to reduce triglycerides
whenever levels exceed 500 mg/dL (5.6 mmol/L).
This reduction can be achieved by addressing and
eliminating the underlying factors as described in
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AND GUIDELINES

Recommendation 1, implementing a very low-
fat diet,S4.5.2-9 and adding fbrates or omega-3
fatty acids for patients with persistently elevated
severe hypertriglyceridemia.S4.5.2-15 These are the
most reliable pharmacological therapies to reduce
triglycerides to a safer level. If a fbrate is neces
sary in a patient being treated with a statin, it is
safer to use fenofbrate than gemfbrozil because
of lower risk of severe myopathy.S4.5.2-16 Severe or
life-threatening hypertriglyceridemia during preg
nancy is best managed in consultation with a lipid
specialist.S4.5.2-17
4.5.3. Issues Specifc to Women
Recommendations for Issues Specifc to Women
Referenced studies that support recommendations are summarized
in Online Data Supplements 33 to 35.
COR
LOE
Recommendations
I
B-NR
1. Clinicians should consider conditions specifc
to women, such as premature menopause
(age <40 years) and history of pregnancy-
associated disorders (hypertension,
preeclampsia, gestational diabetes mellitus,
small-for-gestational-age infants, preterm
deliveries), when discussing lifestyle
intervention and the potential for beneft of
statin therapy.S4.5.3-1-S4.5.3-6
I
C-LD
2. Women of childbearing age who are treated
with statin therapy and are sexually active
should be counseled to use a reliable form of
contraception.S4.5.3-7-S4.5.3-12
I
C-LD
3. Women of childbearing age with
hypercholesterolemia who plan to become
pregnant should stop the statin 1 to 2
months before pregnancy is attempted, or
if they become pregnant while on a statin,
should have the statin stopped as soon as
the pregnancy is discovered.S4.5.3-7-S4.5.3-12
Synopsis
Although atherosclerosis typically occurs later in wom
en than in men, CVD remains the leading cause of
death in women. Statins clearly reduce ASCVD events
in women as well as in men with ASCVD. The 2015
meta-analysis by the CTT Collaboration showed no
heterogeneity by gender for the risk of major vascular
events with statin therapy in participants with a history
of vascular disease.S4.5.3-13 A history of certain pregnan
cy-related conditions and premature menopause (age
<40 years) have been associated with increased ASCVD
risk. However, current best practice emphasizes that
statins should not be taken during pregnancy. Thus,
women of childbearing age who are on statin therapy
and are sexually active should use a reliable form of
contraception to avoid pregnancy. When pregnancy
is planned, stopping statin therapy 1 to 2 months be
fore pregnancy is attempted is suggested as reason
able guidance. When an unplanned pregnancy occurs,
statins should be stopped immediately when the preg
nancy is discovered. Both cholesterol and triglycerides
rise with pregnancy, and those with genetic lipid dis
orders should consider consulting a clinician with lipid
expertise before starting the pregnancy.
Recommendation-Specifc Supportive
Text
1. Several conditions specifc to women (eg, hyper
tensive disorders during pregnancy, preeclampsia,
gestational diabetes mellitus, delivering a preterm
or low-birth-weight infant,S4.5.3-2-S4.5.3-4 and prema
ture menopause [age <40 years]S4.5.3-5,S4.5.3-6,S4.5.3-14)
have been shown to increase ASCVD risk. The
present guideline includes preeclampsia and
premature menopause (age <40 years) as risk-
enhancing factors for statin therapy because they
appear to increase ASCVD risk in the same range
as other risk-enhancing factors. On the other
hand, the mechanism or cause of preterm birth
is often unknown; therefore, it is diffcult to rou
tinely include this condition as a risk-enhancing
factor for statin therapy. Furthermore, if gesta
tional diabetes mellitus predisposes a woman to
metabolic syndrome or diabetes mellitus, these
are already identifed as risk-enhancing or major
ASCVD risk factors. After pregnancy and through
out the life course of every woman, a thorough
pregnancy history should be obtained, and risk
factors and risk-enhancing factors should be
identifed. Interventions should include aggres
sive lifestyle counseling to reduce ASCVD risk and
when appropriate, statin therapy, if ASCVD risk
estimation indicates that the potential for beneft
from statin therapy outweighs the potential for
adverse effects. Decisions should be made in the
context of a risk discussion and should take into
consideration an informed patient preference.
2. All statins are currently contraindicated in pregnant
women, primarily as a result of a 2004 series of
cases of frst-trimester statin exposure reported to
the FDA, which showed 20 cases of malformation,
including 5 severe defects of the central nervous
system and 5 unilateral limb defciencies.S4.5.3-7 In
all cases of adverse birth outcomes, the statin used
was lipophilic. No malformation was identifed in
the 14 infants exposed to pravastatin (hydrophilic).
Since this case series, cohort studies of statin expo
sure in pregnancy did not show an increase in
teratogenic risk,S4.5.3-8-S4.5.3-10 and in fact, the safety
of pravastatin is under study for the prevention of
preeclampsia in high-risk pregnant women.S4.5.3-15
In a meta-analysis of 6 studies of pregnant women
exposed to statins, no increased risk of birth
defects was observed compared with control
subjects. However, there was an increased risk of

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CLINICAL STATEMENTS
AND GUIDELINES

miscarriage in the statin-exposed women versus
controls.S4.5.3-11 Furthermore, in a recent retrospec
tive cohort study that used time-to-event analysis
as a covariate, the adjusted hazard ratio of sponta
neous pregnancy loss in the statin-exposed group
was increased.S4.5.3-12 The increase in miscarriages
may be related to confounders, such as older age,
CVD risk factors, and other medications.
3. A reasonable approach is to stop statins 1 to 2
months before pregnancy is attempted. When
pregnancy is unplanned, statin therapy should
be stopped promptly and not restarted until after
pregnancy and breastfeeding are completed.
Cholesterol levels rise in pregnancy, with a similar
percentage rise in normal women and those with
heterozygous FH. Women with FH do not appear to
have a higher risk of preterm delivery or of having
infants with low birth weight or congenital malfor
mations than unaffected women, but undetected
bias cannot be ruled out.S4.5.3-16 An experienced
lipid specialist should be consulted for women with
homozygous FH whose care is beyond the scope
of the present guideline. Also, triglyceride levels
rise progressively with each trimester, and women
with triglyceride levels >=500 mg/dL (5.6 mmol/L)
at the onset of pregnancy may develop severe
hypertriglyceridemia during the third trimester of
pregnancy, which can lead to pancreatitis.S4.5.3-17
Advising patients on lifestyle (including both diet
and physical activity), optimally managing diseases
like diabetes mellitus and hypothyroidism, and
choosing medications that are less likely to raise tri
glycerides can reduce levels of triglycerides before
pregnancy begins. Treatment of severe hypertri
glyceridemic pregnancy is also beyond the scope
of the present guideline and requires consultation
with an experienced lipid specialist.
4.5.4. Adults With CKD
Recommendations for Adults With CKD
Referenced studies that support recommendations are summarized
in Online Data Supplements 36 to 38.
COR
LOE
Recommendations
IIa
B-R
1. In adults 40 to 75 years of age with LDL-C
70 to 189 mg/dL (1.7 to 4.8 mmol/L) who
are at 10-year ASCVD risk of 7.5% or higher,
CKD not treated with dialysis or kidney
transplantation is a risk-enhancing factor
and initiation of a moderate-intensity statin
or moderate-intensity statins combined with
ezetimibe can be useful.S4.5.4-1,S4.5.4-2
IIb
C-LD
2. In adults with advanced kidney disease that
requires dialysis treatment who are currently
on LDL-lowering therapy with a statin, it may
be reasonable to continue the statin.S4.5.4-2
III: No
Beneft
B-R
3. In adults with advanced kidney disease who
require dialysis treatment, initiation of a
statin is not recommended.S4.5.4-3,S4.5.4-4
Synopsis
CKD is a risk-enhancing factor for ASCVD. In risk dis
cussion with intermediate-risk patients, the presence of
CKD favors initiation of statin therapy. In adults with
advanced kidney disease requiring dialysis treatment
who are currently on pharmacological LDL-lowering
therapy with a statin, it may be reasonable to continue
the statin.S4.5.4-2 In adults with CKD that requires dialysis
treatment, initiation of a statin is not recommended on
the basis of 2 large-scale RCTs.S4.5.4-3,S4.5.4-4
Recommendation-Specifc Supportive
Text
1. Reduced eGFR (<60 mL/min/1.73 m2 not on dialy
sis) and presence of albuminuria (albumin-to
creatinine ratio >=30 mcg/mg) are independently
associated with elevated risk of ASCVD. Hence, in
intermediate-risk patients, CKD counts as a risk-
enhancing factor. According to some studies,S4.5.4-5
the cardiovascular risk for persons with reduced
eGFR may be as high as that observed among
patients with diabetes mellitus and no CKD.
Presence of albuminuria with reduced eGFR
multiplies this CVD risk. The risk is graded and
increases with severity of eGFR impairment, with
observed threshold of risk beginning around 75
mL/min/1.73 m2, whereas the risk associated
with albuminuria is linear.S4.5.4-6 Trials show abso
lute beneft from statin use, and this beneft is
consistent across eGFR stages. However, the RRR
per LDL-C-lowering may be lower with more
advanced CKD. Albuminuria is independently
associated with CVD risk. However, the one trial
done for primary prevention in persons with albu
minuria and preserved eGFR had too few events
to be conclusive.S4.5.4-7
2. According to this recommendation, in patients
with CKD who are currently taking a statin, it
may be reasonable to continue the statin. In sup
port of this, in the SHARP trial (Study of Heart
and Renal Protection) (simvastatin plus ezetimibe
versus placebo), >30% of persons transitioned to
dialysis.S4.5.4-2 After weighting for subgroup-spe
cifc reductions in LDL-C was performed, the pro
portional effects on major atherosclerotic events
were similar in patients on dialysis and those who
were not on dialysis.
3. Although persons on dialysis have the high
est absolute risk of events (and thus poten
tial for higher ARR), the proportion of deaths
thought to be due to atherosclerotic events is
lower.S4.5.4-3,S4.5.4-4 The lack of beneft in RCTs with
statin initiation among persons on dialysis raises the
question of competing risks. Unfortunately, there
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e1116
CLINICAL STATEMENTS
AND GUIDELINES

are not enough data to distinguish the potential
for beneft from statin therapy between those on
peritoneal dialysis and those on hemodialysis.
4.5.5. Adults With Chronic Infammatory
Disorders and HIV
Recommendations for Adults With Chronic Infammatory Disorders
and HIV
Referenced studies that support recommendations are summarized
in Online Data Supplement 39.
COR
LOE
Recommendations
IIa
B-NR
1. In adults 40 to 75 years of age with LDL-C
70 to 189 mg/dL (1.7 to 4.8 mmol/L) who
have a 10-year ASCVD risk of 7.5% or
higher, chronic infammatory disorders
and HIV are risk-enhancing factors and in
risk discussion favor moderate-intensity
statin therapy or high-intensity statin
therapy.S4.5.5-1-S4.5.5-12
IIa
B-NR
2. In patients with chronic infammatory
disorders or HIV, a fasting lipid profle and
assessment of ASCVD risk factors can be
useful as a) a guide to beneft of statin
therapy and b) for monitoring or adjusting
lipid-lowering drug therapy before and 4
to 12 weeks after starting infammatory
disease-modifying therapy or antiretroviral
therapy.S4.5.5-12-S4.5.5-20
IIa
B-NR
3. In adults with RA who undergo ASCVD
risk assessment with measurement of a
lipid profle, it can be useful to recheck
lipid values and other major ASCVD
risk factors 2 to 4 months after the
patient's infammatory disease has been
controlled.S4.5.5-21-S4.5.5-23
Synopsis
Chronic infammatory disorders and HIV infection are
conditions that often enhance risk. Clinicians should
frst focus on helping patients with these diagnoses to
optimize their lifestyle habits. After a 3- to 6-month
trial of lifestyle improvements, including cessation of
cigarette smoking, the patient's 10-year ASCVD risk
estimate should be reassessed. If the patient's ASCVD
risk estimate is >=5% over 10 years, it is reasonable
to begin moderate-intensity statin therapy. If the pa
tient or clinician remains uncertain about the need
for statin therapy or if the patient has had side effects
with a statin in the past, a CAC scan can be used to
improve risk assessment. The absence of CAC in a
nonsmoking man >=40 years of age or a nonsmoking
woman >=45 years of age would indicate that the pa
tient is likely at very low risk of an ASCVD event over
the subsequent decade. Such patients can then focus
on lifestyle habits and delay the decision about statin
therapy for about 5 years. Similarly, a CAC score
>=75th percentile for a patient's age and sex or an ab
solute score >=100 Agatston units would support the
decision to use statin therapy and intensify lifestyle
modifcations.
Recommendation-Specifc Supportive
Text
1. Infammation promotes atherosclerosis and is a
key feature of many chronic rheumatologic infam
matory joint disorders, such systemic lupus ery
thematosus, RA, and psoriasis.S4.5.5-1 Infammation
mediates the progression of atherosclerosis, as
well as instability, erosion, and rupture of vulnera
ble atherosclerotic plaques.S4.5.5-2 Among individu
als with RA, the risk of an MI has been estimated
to be similar to that of an adult with diabetes mel
litus or one who is about 10 years older without
RA.S4.5.5-3 A large meta-analysis found that persons
with RA had an approximately 50% increased
risk of CVD death.S4.5.5-4 Individuals with systemic
lupus erythematosus and advanced psoriasis have
a similarly increased risk of CVD.S4.5.5-5-S4.5.5-7 HIV
infection is associated with an increased risk of
an ASCVD event even if viremia has been con
trolled by antiretroviral therapy.S4.5.5-8 There is an
increased risk of MI in association with long-term
use of antiretroviral therapy, and MI rates are
increased in individuals with HIV.S4.5.5-9 Traditional
ASCVD risk factors, long-term use of antiret
roviral therapy, prolonged immune activation,
and infammation are mediators of atheroscle
rosis progression and development.S4.5.5-9,S4.5.5-10
Coinfection with hepatitis C virus is frequently
present in HIV-infected individuals and further
increases ASCVD risk.S4.5.5-11,S4.5.5-12
2. The accuracy of the ASCVD risk estimator has not
been well validated for adults with chronic infam
matory disorders or HIV infection. Assessment of
traditional risk factors often has resulted in underesti
mation of actual risk and the potential for undertreat
ment with pharmacological therapy.S4.5.5-13,S4.5.5-14
Traditional risk factors should be assessed early in the
disease process and then modifed. Rates of smok
ing in HIV-infected adults have generally been 2 to
3 times that of the general population.S4.5.5-15,S4.5.5-16
Multiple studies have demonstrated underestima
tion of ASCVD risk in patients with chronic infam
matory conditions or HIV.S4.5.5-15,S4.5.5-16 Antiretroviral
therapy may adversely affect lipid levels, glycemic
control, and endothelial functionS4.5.5-17-S4.5.5-19
and has been associated with adverse changes in
body composition (lipodystrophy). However, use of
newer agents may lessen the metabolic derange
ments of antiretroviral therapy. Similarly, the use of
prednisone in chronic infammatory diseases may
worsen glycemic control and dyslipidemia.S4.5.5-20
The most common lipid abnormality phenotype in
persons with HIV infection is an elevated triglycer
ide level with a low HDL-C. In HIV-infected adults,

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CLINICAL STATEMENTS
AND GUIDELINES

triglycerides should preferentially be measured in
the fasting state.
3. Patients with RA who are untreated or who have
high disease activity generally have decreased levels
of TC, triglycerides, HDL-C, and LDL-C.S4.5.5-21 These
lower lipid levels are likely attributable in part to
increased infammation and may lead to functional
proatherogenic changes, such as decreased cho
lesterol effux capacity of HDL-C.S4.5.5-22 Treatment
with anti-infammatory medications, such as tumor
necrosis factor alpha inhibitors or methotrexate, is
associated with an increase in and normalization
of lipid levels and a reduction in the ratio of TC
to HDL-C.S4.5.5-23 Thus, to produce a more accurate
risk estimate, ASCVD risk estimation should be
repeated when the patient has a stable and low
disease activity with normalization of their lipid lev
els; lower lipid levels measured during high disease
activity may lead to a signifcant underestimation
of ASCVD risk for patients with RA.
5. STATIN SAFETY AND STATIN
ASSOCIATED SIDE EFFECTS
Recommendations for Statin Safety and Statin-Associated Side
Effects
Referenced studies that support recommendations are summarized
in Online Data Supplements 40 and 41.
COR
LOE
Recommendations
I
A
1. A clinician-patient risk discussion is
recommended before initiation of statin
therapy to review net clinical beneft, weighing
the potential for ASCVD risk reduction against
the potential for statin-associated side effects,
statin-drug interactions, and safety, while
emphasizing that side effects can be addressed
successfully.S5-1-S5-7
I
A
2. In patients with statin-associated muscle
symptoms (SAMS), a thorough assessment
of symptoms is recommended, in addition
to an evaluation for nonstatin causes and
predisposing factors.S5-3-S5-7
I
B-R
3. In patients with indication for statin therapy,
identifcation of potential predisposing
factors for statin-associated side effects,
including new-onset diabetes mellitus and
SAMS, is recommended before initiation of
treatment.S5-3-S5-7
I
B-R
4. In patients with statin-associated side effects
that are not severe, it is recommended
to reassess and to rechallenge to achieve
a maximal LDL-C lowering by modifed
dosing regimen, an alternate statin or in
combination with nonstatin therapy.S5-3-S5-8
I
B-R
5. In patients with increased diabetes mellitus
risk or new-onset diabetes mellitus, it is
recommended to continue statin therapy,
with added emphasis on adherence, net
clinical beneft, and the core principles of
regular moderate-intensity physical activity,
maintaining a healthy dietary pattern, and
sustaining modest weight loss.S5-8-S5-12
Synopsis
Recommendations for Statin Safety and Statin-Associated Side
Effects (Continued)
COR
LOE
Recommendations
I
C-LD
6. In patients treated with statins, it is
recommended to measure creatine kinase
levels in individuals with severe statin
associated muscle symptoms, objective
muscle weakness, and to measure liver
transaminases (aspartate aminotransferase,
alanine aminotransferase) as well as total
bilirubin and alkaline phosphatase (hepatic
panel) if there are symptoms suggesting
hepatotoxicity.S5-13-S5-15
I
B-R
7. In patients at increased ASCVD risk with
chronic, stable liver disease (including
non-alcoholic fatty liver disease) when
appropriately indicated, it is reasonable
to use statins after obtaining baseline
measurements and determining a schedule
of monitoring and safety checks.S5-16-S5-18
IIa
B-R
8. In patients at increased ASCVD risk with
severe statin-associated muscle symptoms or
recurrent statin-associated muscle symptoms
despite appropriate statin rechallenge, it
is reasonable to use RCT proven nonstatin
therapy that is likely to provide net clinical
beneft.S5-5,S5-6,S5-19
III: No
Beneft
B-R
9. Coenzyme Q10 is not recommended for
routine use in patients treated with statins or
for the treatment of SAMS.S5-20,S5-21
III: No
Beneft
C-LD
10. In patients treated with statins, routine
measurements of creatine kinase and
transaminase levels are not useful.S5-13-S5-15
Statin therapy is usually well tolerated and safe.S5-1,S5-14,
S5-22-S5-24 As with other classes of medications, associ
ated side effects are seen. Instead of the label statin
intolerance, the present guideline prefers statin-associ
ated side effects because the large majority of patients
are able to tolerate statin rechallenge with an alterna
tive statin or alternative regimen, such as reduced dose
or in combination with nonstatins. Although infrequent
or rare in clinical trials, statin-associated side effects
can be challenging to assess and manage.S5-25,S5-26 The
most frequent are SAMS. SAMS usually are subjective
myalgia, reported observationally in 5% to 20% of
patients.S5-11-S5-14 SAMS often result in nonadherence
adversely impact ASCVD outcomes.S5-27-S5-29
and can
Statins modestly increase risk of incident diabetes mel
litus in susceptible individuals,S5-8-S5-11 but this should
not be cause for discontinuation (Table 11). The present
guideline recommends a comprehensive approach to
statin-associated symptoms. The clinician should reas
sess, rediscuss, and encourage rechallenge as the ini
tial approach unless side effects are severe. Ongoing
communication is integral to patient care, as is regular
monitoring to check for adherence, adequacy of re
sponse, new associated symptoms, and reaffrmation
of beneft.S5-2
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Table 11. Statin-Associated Side Effects (SASE)
Statin-Associated Side Effects
Frequency
Predisposing Factors
Quality of
Evidence
Statin-associated muscle symptoms (SAMS)
Myalgias (CK normal)
Infrequent (1% to 5%) in RCTs; frequent (5% to
10%) in observational studies and clinical setting
Age, female sex, low body mass
index, high-risk medications (CYP3A4
inhibitors, OATP1B1 inhibitors),
comorbidities (HIV, renal, liver, thyroid,
preexisting myopathy), Asian ancestry,
excess alcohol, high levels of physical
activity, and trauma
RCTs cohorts/
observational
Myositis/myopathy (CK > ULN) with
concerning symptoms or objective
weakness
Rare
RCTs cohorts/
observational
Rhabdomyolysis (CK >10x ULN + renal
injury)
Rare
RCTs cohorts/
observational
Statin-associated autoimmune myopathy
(HMGCR antibodies, incomplete resolution)
Rare
Case reports
New-onset diabetes mellitus
Depends on population; more frequent if diabetes
mellitus risk factors are present, such as body mass
index >=30, fasting blood glucose >=100 mg/dL;
metabolic syndrome, or A1c >=6%.
Diabetes mellitus risk factors/metabolic
syndrome
RCTs/meta-analyses
High-intensity statin therapy
Liver
Transaminase elevation 3x ULN
Infrequent
RCTs/cohorts/
observational
Case reports
Hepatic failure
Rare
Central nervous system
Memory/cognition
Rare
Case reports; no
increase in memory/
cognition problems
in 3 large-scale RCTs
Cancer
No defnite association
RCTs/meta-analyses
Other
Renal function
Unfounded
Cataracts
Unfounded
Tendon rupture
Unfounded
Hemorrhagic stroke
Unfounded
Interstitial lung disease
Unfounded
Low testosterone
Unfounded
CK indicates creatine kinase; HIV, human immunodefciency virus; HMGCR, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; SAMS, statin-associated muscle
symptoms; SAAM, statin-associated autoimmune myopathy; SASE, statin associated side effects; and ULN, upper limit of normal.
Recommendation-Specifc Supportive
Text
1. A clinician-patient risk discussion focused on indi
cations, benefts, risks of statin-associated side
effects, and patient concerns and preferences
should precede initiation of statin treatment.S5-2
This dialogue is the foundation of a longitudinal
care partnership that is based on informed deci
sion-making. Future encounters should address
statin response, emphasize adherence, and reaf
frm beneft. Statin-associated symptoms should
be comprehensively assessed, and because most
can be well managed,S5-3-S5-7 the goal should be to
optimize patient-centered strategies for ASCVD
prevention.
2. The majority of SAMS are subjective myalgia (pain,
aches) in the absence of other fndings.S5-13,S5-25,S5-30
Myalgia is more likely to be statin associated if it is
bilateral, involves proximal muscles, has its onset
within weeks to months after initiation of statins,
and resolves after discontinuation of statins.S5-13,S5-14
A thorough assessment of symptoms is recom
mended, in addition to evaluation for nonstatin
etiologies, assessment of predisposing factors,
and a physical exam. Objective muscle weakness

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(myopathy) and associated signifcant increase in
CK (myositis) are rareS5-1,S5-22,S5-30 but require prompt
statin cessation and evaluation for reversible
causes. Rhabdomyolysis (CK >10 times upper limit
of normal, with evidence of renal injury) is exceed
ingly rare and usually encountered in the setting of
a patient with several predisposing comorbidities
and concomitant high-risk medications.S5-1,S5-22,S5-30
It requires immediate medical attention.
3. Before lipid-lowering therapy with a statin is
initiated, a comprehensive evaluation of mus
culoskeletal symptoms (with documentation) is rec
ommended because such symptoms are common
at baseline in the general adult population.S5-3-S5-6
Before therapy, it is also important to identify predis
posing factors for SAMS, including demographics,
comorbid conditions, and use of medications that
can adversely affect statin metabolismS5-3,S5-13,S5-14
(Table 11). Proactive and preemptive identifcation
of patients at potential increased risk of statin
associated side effects should help guide informed
clinical decision-making and is supportive of the
goals of safe and effective therapy.
4. Several creatively designed randomized crossover
trials in patients with SAMSS5-3-S5-7 support a man
agement strategy of statin discontinuation until
symptoms improve, followed by rechallenge with
a reduced dose, alternative agent, or alternative
dosing regimen while monitoring for recurrent
symptoms. If the approach of reassess, rediscuss
(net clinical beneft), and rechallenge is used, a
majority of patients will be able to be successfully
treated with at least one or several statins.S5-29,S5-31
In patients at increased ASCVD risk, the goal should
be to treat with the guideline-recommended max
imally tolerated statin dose. Patients who experi
ence rhabdomyolysis with statin therapy may need
to discontinue statin use indefnitely, although
reversible causes should be sought.S5-32 Clinicians
should be aware of a rare disorder, statin-associ
ated autoimmune myopathy (muscle weakness,
marked and persistent CK elevation, presence
of HMG CoA reductase [HMGCR] antibodies,
necrotizing myopathy, and lack of or incomplete
resolution on statin discontinuation), that requires
statin cessation and additional therapy directed at
the autoimmune process.S5-32 Patients with statin
associated autoimmune myopathy may beneft
from seeing a neurologist specializing in neuro
muscular disorders.
5. Evidence indicates that statins modestly increase
the risk of incident or statin-associated new-onset
diabetes mellitus in individuals with predisposing
risk factors for diabetes mellitus, components of
the metabolic syndrome, and higher-intensity statin
use.S5-8-S5-11 The specifc mechanisms leading to
statin-associated diabetes mellitus remain unclear,
although it is unlikely that statins directly cause
diabetes mellitus. Rather, it appears that a small
number of individuals with diabetic susceptibility
cross the threshold to incident diabetes mellitus
after statin therapy. is initiated It is important that
patients are informed of the potential risk of new-
onset diabetes mellitus before initiation of statin
therapy. Because the benefts of statin therapy are
shown to outweigh the risks of new-onset diabetes
mellitus, the possibility of incident diabetes mellitus
should not be a contraindication to statin therapy
or indication for statin discontinuation.S5-8,S5-14,S5-33
In individuals at increased risk of both ASCVD and
incident diabetes mellitus, it is recommended that
counseling based on the ADA prevention approach
be provided. This approach encourages regular
moderate physical activity, maintaining a healthy
dietary pattern, and sustaining modest weight loss
(according to the core principles of the Diabetes
Prevention Program).S5-12
6. In patients with statin-associated side effects, it is
recommended that CK be measured in the case of
severe SAMS and in the presence of objective mus
cle weakness. After baseline liver transaminases, the
FDA recommends measuring transaminases (aspar
tate aminotransferase [serum glutamic-oxaloacetic
transaminase] and alanine aminotransferase [serum
glutamic-pyruvic transaminase]) if there are signs or
symptoms suggesting hepatotoxicity.S5-13-S5-15
7. An asymptomatic increase in transaminases (>3 times
upper limit of normal) is an infrequent statin-associ
ated side effect that often resolves with dose reduc
tion or rechallenge with alternative statins.S5-1,S5-22
Severe statin-associated hepatotoxicity is rare, and
the incidence is not impacted by routine monitor
ing of transaminases.S5-34 A thorough evaluation
for nonstatin etiologies is warranted when signif
cant transaminase elevation persists. Importantly,
statins are not contraindicated in patients with
increased ASCVD risk with chronic, stable liver dis
ease (eg, nonalcoholic fatty liver), and limited data
suggest potential beneft.S5-16-S5-18
8. Severe statin-associated side effects are rare, and
recurrent SAMS are infrequent when a thorough
reassessment and management strategy of reas
sess, rediscuss, and rechallenge is used. In patients
at increased ASCVD risk with severe statin-asso
ciated side effects or recurrent SAMS, nonstatin
therapy should be considered when there is net
clinical beneft.S5-5,S5-6,S5-19
9. The clinical diagnosis of SAMS remains chal
lenging, given that the majority of symptoms
are subjective and defnitive diagnostic criteria
do not exist.S5-13 Multiple potential mechanisms
have been suggested to contribute to SAMS,
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including depletion of ubiquinone or coenzyme
Q10. Available evidence, however, does not sup
port the use of coenzyme Q10 supplementation
for routine use in patients treated with statins or
for the treatment of SAMS.S5-20,S5-21
10. The majority of SAMS are subjective myalgia in
the absence of other fndings,S5-3,S5-13,S5-14,S5-23,S5-30
and an asymptomatic increase in transaminases
(>3 times upper limit of normal) is an infrequent
statin-associated side effect.S5-1,S5-22,S5-24 Therefore,
CK and transaminase levels should not be rou
tinely measured given the unlikely impact on
clinical outcomes, and the lack of established cost
effectiveness.S5-15
6. IMPLEMENTATION
Recommendations for Implementation
Referenced studies that support recommendations are summarized
in Online Data Supplements 42 to 46.
COR
LOE
Recommendations
I
A
1. Interventions focused on improving
adherence to prescribed therapy are
recommended for management of adults
with elevated cholesterol levels, including
telephone reminders, calendar reminders,
integrated multidisciplinary educational
activities, and pharmacist-led interventions,
such as simplifcation of the drug regimen to
once-daily dosing.S6-1-S6-4
I
B-NR
2. Clinicians, health systems, and health
plans should identify patients who are
not receiving guideline-directed medical
therapy and should facilitate the initiation
of appropriate guideline-directed medical
therapy, using multifaceted strategies to
improve guideline implementation.S6-5,S6-6
I
B-NR
3. Before therapy is prescribed, a patient-
clinician discussion should take place to
promote shared decision-making and
should include the potential for ASCVD risk-
reduction beneft, adverse effects, drug-drug
interactions, and patient preferences.S6-7,S6-8
Synopsis
Guideline publication does not guarantee guideline
implementation. Healthcare delivery is complex, and
barriers to guideline implementation can occur at the
patient, clinician, health system, and health plan levels,
leading to gaps in care. A more concerted effort, with
multifaceted strategies aimed at the patient, clinician,
health system, and health plan, is needed to overcome
the barriers and achieve wider guideline implementa
tion (Table S7). The patient is a key player in success
ful guideline implementation, and the clinician-patient
discussion is crucial to the successful initiation and con
tinuation of guideline-directed management and thera
py (Table 7). As part of the clinician-patient discussion,
the patient should be encouraged to state what was
heard, ask questions, express values and preferences,
and state ability and willingness to adhere to lifestyle
changes and medications. This is where a discussion
of out-of-pocket costs can occur. Clinicians should use
multiple interventions to promote adherence, including
asking more specifc questions about adherence, aim
ing for once-daily dosing, using automated reminders,
participating in multidisciplinary educational activities,
and using pharmacist-led interventions.
Recommendation-Specifc Supportive
Text
1. Interventions focused on improving adherence to
prescribed therapy are recommended for man
agement of adults with elevated cholesterol lev
els. A Cochrane systematic review demonstrated
that intensifcation of patient care interventions
improves both short- and long-term adherence
to medication, as well as meaningful reduction
in LDL-C levels. Interventions include telephone
reminders, calendar reminders, integrated mul
tidisciplinary educational activities, simplifcation
of the drug regimen to once-daily dosing, and
pharmacist-led interventions.S6-1-S6-4 Clinicians may
wish to review Table S7 in the Web Supplement,
"Strategies to Improve Guideline Implementation
by Setting and Target Audience Measures to
Improve Lipid Medication Adherence."
2. Clinicians do not follow guidelines for many
reasons,S6-9 and cholesterol guideline implementation
has not been optimal.S6-10-S6-13 Interventions aimed
at the clinician may improve guideline implemen
tation. Educational outreach or academic detailing
visits are generally effective for improving process-
of-care, clinical, cost-reduction, and cost-effec
tiveness outcomes.S6-5 Audits of individual clinical
performance and feedback are generally effective in
improving process-of-care and clinical outcomes.S6-5
Reminders and individual pay-for-performance are
generally effective for cost reduction.S6-5
Even if guideline-directed management and
therapy are prescribed, patients may be nonadher
ent or not get the prescribed medication for a vari
ety of reasons.S6-14 Patients who are initially adherent
to statin therapy may not demonstrate long-term
adherence.S6-15,S6-16 Adherent patients, with and
without clinical ASCVD, have improved outcomes
and reduced costs.S6-15,S6-17-S6-20 Formulary restrictions
and prior authorization requirements have been
associated with care delays and nonadherence.S6-21
Interventions aimed at the patient may improve
adherence and clinical outcomes.
Guideline implementation strategies that are
aimed at the patient, clinician, health system,
and health plan are needed. Barriers to guideline

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implementation should be analyzed in advance,
and implementation strategies should be tailored
to the setting and target audience. Multiple strat
egies may be needed to effectively implement
guidelinesS6-5,S6-6 (Table S7 in the Web Supplement).
3. Patients who participate in shared decision-making
may have better health outcomes, better health
care experiences, and lower costs.S6-7,S6-8 During
the clinician-patient risk discussion with shared
decision-making, the patient participates with the
clinician in deciding lifestyle modifcations, medica
tion treatment, and goals of therapy. The clinician
should explain the patient's risk of clinical ASCVD
and how the treatment recommendations reduce
ASCVD risk. The patient should verbalize values,
attitudes, abilities, concerns, and personal goals for
making lifestyle changes and taking medications,
including concerns about cost.S6-22 The clinician may
use a checklist to facilitate shared decision-making
with the patient (Table S8 in the Web Supplement).
The clinician should use tools and techniques
to support shared decision-making.S6-7,S6-22-S6-26
Decision aids may allow the patient to be more
knowledgeable, have better risk perception, and
have a clearer understanding of their values.S6-8,S6-27
Question prompt lists may increase knowledge by
including questions about the purpose or goal of
treatment, the risk with and without treatment,
how the medication should be taken, potential side
effects and how to manage them, when to notify the
offce, and monitoring and follow-up. Motivational
interviewingS6-28 and decision coaching may also
promote patient knowledge and satisfaction.
7. COST AND VALUE CONSIDERATIONS
7.1. Economic Value Considerations:
PCSK9 Inhibitors
ACC/AHA clinical guidelines now recognize the im
portance of considering economic value in making
recommendations, in accordance with the principles
established by an expert group.S7.1-1 PCSK9 inhibi
tors further reduce LDL-C when combined with other
LDL-lowering drugs, and they reduced composite car
diovascular events in 2 RCTs of high-risk, secondary-
prevention patients with clinical ASCVD.S7.1-2 The cost-
effectiveness and economic value of PCSK9 inhibitors
have been assessed by using simulation models (Online
Data Supplements 47 and 48); the published models
are based on different sets of assumptions. Compared
with statin therapy for secondary prevention, PCSK9
inhibitors have incremental cost-effectiveness ratiosS7.1-3
from $141700 to $450000 per quality-adjusted life-
year (QALY) added, at mid-2018 list prices. None of the
published models report "good value" (<$50000 per
Table 12. Proposed Integration of Level of Value Into Clinical
Guideline Recommendations*
Level of Value
High value: Better outcomes at lower cost or ICER <$50000 per QALY gained
Intermediate value: $50000 to <$150 000 per QALY gained
Low value: >=$150000 per QALY gained
Uncertain value: Value examined, but data are insuffcient to draw a
conclusion because of absence of studies, low-quality studies, conficting
studies, or prior studies that are no longer relevant
Not assessed: Value not assessed by the writing committee
Proposed abbreviations for each value recommendation:Level of value:
H to indicate high value; I, intermediate value; L, low value; U, uncertain
value; and NA, value not assessed.
*Dollar amounts used in this table are based on US GDP data from 2012
and were obtained from WHO-CHOICE Cost-Effectiveness Thresholds.S7.1-9
Reproduced from Anderson et al.S7.1-1
GDP indicates gross domestic product; ICER, incremental cost-effectiveness
ratio; QALY, quality-adjusted life-years; and WHO-CHOICE, World Health
Organization Choosing Interventions that are Cost-Effective.
QALY added; Table 12), and virtually all indicate "low
value" (>=$150000 per QALY added). All models pro
jected mortality beneft by assuming that mortality rate
reductions either parallel LDL-C loweringS7.1-4 or parallel
RRRs for nonfatal ASCVD events.
All models project higher lifetime cost from use of
PCSK9 inhibitors because the cost will exceed any sav
ings from prevention of cardiovascular events. To be
cost-effective by conventional standards, the cost of
PCSK9 inhibitors will have to be reduced on the order
of 70% to 85% in the United States.S7.1-3 At any given
price, the economic value of PCSK9 inhibitors will be
improved by restricting their use to patients at very
high-risk of ASCVD events, as recommended in the
present guidelines. The inverse relationship between
improved survival and the incremental cost-effective
ness ratio (Figure 3) indicates that the economic val
ue of PCSK9 inhibitors will be improved by selecting
higher-risk patients. One simulation model suggested
that restricting the use of PCSK9 inhibitor therapy to
patients with baseline LDL-C levels >=119 mg/dL (>=3
mmol/L), instead of >=70 mg/dL (>=1.8 mmol/L), would
improve their cost-effectiveness to $150 000 per QALY
added, instead of $268 000.S7.1-5 Another study pro
jected a similar improvement in economic value.S7.1-6
Thus, raising the threshold for LDL-C on maximal
statin therapy to initiate a PCSK9 inhibitor should im
prove its cost-effectiveness (Figure 3).
Only 2 economic models have specifcally examined
the value provided by PCSK9 inhibitors for primary pre
vention in patients with heterozygous FH (Online Data
Supplement 45). One modelS7.1-7 found low value when
PCSK9 inhibitors were used for FH ($503000 per QALY
added), whereas the second modelS7.1-8 reported inter
mediate value (incremental cost-effectiveness ratio of
$75900 per QALY added). Consequently, the value of
PCSK9 inhibitor therapy in FH is uncertain.
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Figure 3. Cost-effectiveness analysis for PCSK9 inhibitors.
Conceptual relationship between the clinical effectiveness of PCSK9 inhibitor therapy, measured in QALYs added compared with statin therapy, on the horizontal
axis, and their clinical value, measured in dollars per QALY added, on the vertical axis. The top curve indicates the relationship at full U.S list price of PCSK9 inhibi
tor therapy ($14000/y), the middle curve indicates the relationship if the price were reduced by 50% (ie, to $7 000/y), and the bottom curve indicates the relation
ship if the price were reduced by 75% (ie, to $3 500/y). Reproduced from Hlatky et al.S7.1-3 CV indicates cardiovascular; and QALY, quality-adjusted life-years.
8. LIMITATIONS AND KNOWLEDGE
GAPS
8.1. Randomized Controlled Trials
ACC/AHA guidelines are based largely on the outcomes
of RCTs. Cholesterol guidelines have fortunately benefted
from a large number of RCTs of cholesterol-lowering thera
pies. They have established that greater reductions of LDL
C are accompanied by greater reductions in risk of ASCVD.
Robust RCTs exist for both primary and secondary preven
tion. Most of the data from RCTs have been obtained with
statin therapy. Important limited data have also been ob
tained with nonstatins as add-on drugs to statin therapy.
Nevertheless, more data are needed to determine the full
scope of the beneft of nonstatin drugs. Several important
questions need to be addressed by additional RCTs.
1. In secondary prevention, does a lower limit for
LDL-C attainment exist, beyond which the incre
mental beneft attained is worth neither the risks
nor the cost of additional therapy?
2. In secondary prevention, what are the indications
for adding PCSK9 inhibitors to maximal statin
therapy?
3. In patients with ASCVD who have statin-associ
ated side effects, are PCSK9 inhibitors an effective
and safe substitute for high-intensity statins?
4. In primary prevention for adults 45 to 75 years
of age (LDL-C <90 mg/dL [<2.3 mmol/L]) with or
without diabetes mellitus, what is the incremental
risk reduction imparted by high-intensity statins
as compared with moderate-intensity statins?
5. In primary prevention for adults 45 to 75 years of
age (LDL-C <190 mg/dL [<4.9 mmol/L]) with or
without diabetes mellitus, what is the incremen
tal risk reduction imparted by moderate-intensity
statins plus ezetimibe as compared with moder
ate-intensity statins alone?
6. Is statin therapy effcacious and safe in older
patients (>75 years of age)? If so, what is a net
beneft of statin therapy in this age group?
7. In patients with severe hypercholesterolemia, what
are the effcacy and net beneft of PCSK9 inhibitors
as add-on treatment to maximal statin therapy?
8. What is the effcacy of moderate-intensity and
high-intensity statin therapy in patients with risk-
enhancing factors (eg, chronic infammatory dis
ease, CKD, metabolic syndrome)?
8.2. Risk Assessment
In primary prevention, the appropriate selection of pa
tients for cholesterol-lowering drug therapy is highly de
pendent on risk assessment. Previous guidelines made

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use of risk-assessment algorithms (eg, Framingham risk
scoring or PCE) to estimate risk. Although these equa
tions are useful, they may overestimate or underesti
mate risk for individual patients. For this reason, the
2013 ACC/AHA guidelinesS8.2-1 introduced the clinician-
patient risk discussion to facilitate clinical decisions
about appropriate therapy. In the present guidelines,
the clinician-patient risk discussion has been amplifed
and made an integral part of the clinical decision. In
addition, in cases in which uncertainty exists, the mea
surement of CAC has been proposed as a third step in
making a treatment decision. Each of these steps could
be improved for future guidelines.
8.2.1. Continuing Refnement of PCE
Because the population baseline risk may be continually
declining in the US population, ongoing epidemiological
study is needed to assess and update population risk. An
example is the development of QRISK in the U.K. popula
tion, which is continually expanding its scope.
8.2.2. Improvement in Lifetime Risk Estimate
The present guidelines include a lifetime ASCVD risk al
gorithm for those 20 to 59 years of age, but it is based
on an insuffcient database. Along with a risk algorithm
for short-term risk of ASCVD (eg, 10 years), a more
robust lifetime risk algorithm would facilitate the clini
cian-patient risk discussion for treatment decisions.
8.2.3. Refnement of Clinician-Patient Risk
Discussion
An ongoing study of how a clinician can best interact
with a patient to arrive at an informed decision must be
done, taking multiple factors into consideration. This
is particularly important because cholesterol-lowering
therapy is meant to be a lifetime therapy.
8.2.4. Monitoring and Adjustment of Treatment
The clinician-patient risk discussion will likely prove in
adequate unless an ongoing interaction between the
patient and clinician occurs. This involves monitoring
the effectiveness of therapy and adherence to therapy.
Thus, the clinician-patient risk discussion should in
clude more than the initial treatment decision. Ongoing
research on how to improve the entire process of initial
decision-making and long-term follow-up is necessary.
8.2.5. Prognostic Signifcance of CAC
The present guideline makes use of the available data
to predict the risk associated with CAC. These data
need to be amplifed by new and ongoing studies to
guide treatment decisions. Particular uncertainty exists
about the predictive value of intermediate CAC scores.
In addition, the predictive signifcance of a CAC score
of zero must be further verifed in follow-up studies. For
patients with a CAC score of zero, it is currently uncer
tain when and if follow-up CAC measurements should
be done to reassess risk status.
ACC/AHA TASK FORCE MEMBERS
Glenn N. Levine, MD, FACC, FAHA, Chair; Patrick T.
O'Gara, MD, MACC, FAHA, Chair-Elect; Jonathan L.
Halperin, MD, FACC, FAHA, Immediate Past Chair*;
Sana M. Al-Khatib, MD, MHS, FACC, FAHA; Joshua A.
Beckman, MD, MS, FAHA; Kim K. Birtcher, PharmD, MS,
AACC; Biykem Bozkurt, MD, PhD, FACC, FAHA*; Ralph
G. Brindis, MD, MPH, MACC*; Joaquin E. Cigarroa, MD,
FACC; Lesley H. Curtis, PhD, FAHA*; Anita Deswal, MD,
MPH, FACC, FAHA; Lee A. Fleisher, MD, FACC, FAHA;
Federico Gentile, MD, FACC; Samuel Gidding, MD,
FAHA*; Zachary D. Goldberger, MD, MSc, FACC, FAHA;
Mark A. Hlatky, MD, FACC, FAHA; John Ikonomidis, MD,
PhD, FAHA*; Jose A. Joglar, MD, FACC, FAHA; Laura
Mauri, MD, MSc, FAHA*; Mariann R. Piano, RN, PhD,
FAHA; Susan J. Pressler, PhD, RN, FAHA*; Barbara Riegel,
PhD, RN, FAHA*; Duminda N. Wijeysundera, MD, PhD
PRESIDENTS AND STAFF
American College of Cardiology
C. Michael Valentine, MD, FACC, President
Timothy W. Attebery, MBA, FACHE, Chief Executive
Offcer
William J. Oetgen, MD, MBA, FACC, Executive Vice Presi
dent, Science, Education, Quality, and Publishing
MaryAnne Elma, MPH, Senior Director, Science, Educa
tion, Quality, and Publishing
Amelia Scholtz, PhD, Publications Manager, Science,
Education, Quality, and Publishing
American College of Cardiology/
American Heart Association
Katherine A. Sheehan, PhD, Director, Guideline Strat
egy and Operations
Abdul R. Abdullah, MD, Senior Manager, Guideline
Science
Thomas S.D. Getchius, Manager, Guideline Operations
American Heart Association
Ivor Benjamin, MD, FAHA, President
Nancy Brown, Chief Executive Offcer
Rose Marie Robertson, MD, FAHA, Chief Science and
Medicine Offcer
Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice
President, Offce of Science Operations
Prashant Nedungadi, PhD, Science and Medicine Advi
sor, Offce of Science Operations
Jody Hundley, Production and Operations Manager, Sci
entifc Publications, Offce of Science Operations
*Former Task Force member; current member during the
writing effort.
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e1124
CLINICAL STATEMENTS
AND GUIDELINES

ARTICLE INFORMATION
This document was approved by the American College of Cardiology Clinical
Policy Approval Committee, the American Heart Association Science Advisory
and Coordinating Committee, American Association of Cardiovascular and
Pulmonary Rehabilitation, American Academy of Physician Assistants, Associa
tion of Black Cardiologists, American College of Preventive Medicine, American
Diabetes Association, American Geriatrics Society, American Pharmacists Asso
ciation, American Society for Preventive Cardiology, National Lipid Association,
and Preventive Cardiovascular Nurses Association in October 2018, and the
American Heart Association Executive Committee in October 2018.
Supplemental materials are available with this article at https://www.
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AND GUIDELINES

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AND GUIDELINES

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4. PATIENT MANAGEMENT GROUPS
4.1. Secondary ASCVD Prevention
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June 18/25, 2019
CLINICAL STATEMENTS
AND GUIDELINES

S4.1-14. Bohula EA, Morrow DA, Giugliano RP, et al. Atherothrombotic risk
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S4.1-16. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a ran
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tCookieSupport=1. Accessed March 27, 2018.
7. COST AND VALUE CONSIDERATIONS
7.1. Economic Value Considerations:
PCSK9 Inhibitors
S7.1-1. Anderson JL, Heidenreich PA, Barnett PG, et al. ACC/AHA state
ment on cost/value methodology in clinical practice guidelines
and performance measures: a report of the American College of
Cardiology/American Heart Association Task Force on Performance
Measures and Task Force on Practice Guidelines. Circulation.
2014;129:2329-45.
S7.1-2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clini
cal outcomes in patients with cardiovascular disease. N Engl J Med.
2017;376:1713-22.
S7.1-3. Hlatky MA, Kazi DS. PCSK9 Inhibitors: economics and policy. J Am
Coll Cardiol. 2017;70:2677-87.
S7.1-4. Baigent C, Keech A, Kearney PM, et al. Effcacy and safety of
cholesterol-lowering treatment: prospective meta-analysis of data
from 90056 participants in 14 randomised trials of statins. Lancet.
2005;366:1267-78.
S7.1-5. Fonarow GC, Keech AC, Pedersen TR, et al. Cost-effectiveness of evo
locumab therapy for reducing cardiovascular events in patients with ath
erosclerotic cardiovascular disease. JAMA Cardiol. 2017;2:1069-78.
S7.1-6. Robinson JG, Huijgen R, Ray K, et al. Determining when to add
nonstatin therapy: a quantitative approach. J Am Coll Cardiol.
2016;68:2412-21.
S7.1-7. Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9
inhibitor therapy in patients with heterozygous familial hypercho
lesaaaaaaaaterolemia or atherosclerotic cardiovascular disease.
JAMA. 2016;316:743-53.
S7.1-8. Gandra SR, Villa G, Fonarow GC, et al. Cost-effectiveness of LDL-C
lowering with evolocumab in patients with high cardiovascular risk
in the United States. Clin Cardiol. 2016;39:313-20.
S7.1-9. Choosing interventions that are cost effective (WHO-CHOICE):
cost-effectiveness thresholds. Geneva, Switzerland: World Health
Organization, 2009.
8. LIMITATIONS AND KNOWLEDGE
GAPS
8.2. Risk Assessment
S8.2-1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA
guideline on the treatment of blood cholesterol to reduce ath
erosclerotic cardiovascular risk in adults: a report of the American
College of Cardiology/American Heart Association Task Force on
Practice Guidelines. Circulation. 2014;129:S1-45.

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CLINICAL STATEMENTS
AND GUIDELINES

Appendix 1. Author Relationships With Industry and Other Entities (Relevant)-2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/
NLA/PCNA Guideline on the Management of Blood Cholesterol* (August 2018)
Committee
Member
Employment
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Beneft
Expert
Witness
Scott M. Grundy
Chair
VA North Texas Health Care System and
University of Texas Southwestern Medical
Center at Dallas-Professor of Internal
Medicine
None
None
None
None
None
None
Neil J. Stone
Vice Chair
Northwestern Medicine/Northwestern
University-Bonow Professor of
Medicine, Cardiology
None
None
None
None
None
None
Alison L. Bailey
Erlanger Health System/University
of Tennessee College of Medicine-
Program Director, Cardiovascular
Diseases Fellowship; Director, Preventive
cardiology and Cardiac Rehabilitation
None
None
None
None
None
None
Craig Beam
CBRE-Managing Director; National
Cultivation/Strategic Investments Leader
None
None
None
None
None
None
Kim K. Birtcher
University of Houston College of
Pharmacy-Clinical Professor
None
None
None
None
None
None
Roger S.
Blumenthal
Johns Hopkins University, Ciccarone
Center for the Prevention of Heart
Disease-Professor of Medicine
None
None
None
None
None
None
Lynne T. Braun
Rush University Medical Center-
Professor of Nursing and Medicine
None
None
None
None
None
None
Sarah De Ferranti
Boston Children's Hospital- of Pediatrics
None
None
None
None
None
None
Joseph Faiella-
Tommasino
Touro College, School of Health
Sciences-Chairman and Assistant Dean
of Physician Assistant Programs
None
None
None
None
None
None
Daniel E. Forman
University of Pittsburgh-Chair, Geriatric
Cardiology
None
None
None
None
None
None
Ronald Goldberg
University of Miami, Diabetes Research
Institute-Professor of Medicine, Division
of Endocrinology, Metabolism and
Diabetes
None
None
None
None
None
None
Paul A. Heidenreich
Stanford University, Department of
Medicine-Professor, Vice Chair for
Quality
None
None
None
None
None
None
Mark A. Hlatky
Stanford University, School of Medicine-
Professor of Health Research Policy,
Professor of Cardiovascular Medicine
None
None
None
None
None
None
Daniel W. Jones
University of Mississippi Medical
Center-Professor of Medicine and
Physiology; Director, Clinical and
Population Science
None
None
None
None
None
None
Donald Lloyd-Jones
Northwestern University-Eileen M.
Foell Professor; Chair, Department of
Preventive Medicine
None
None
None
None
None
None
Nuria Lopez-Pajares
Temple University-Physician
None
None
None
None
None
None
Chiadi Ndumele
Johns Hopkins University School of
Medicine-Robert E. Meyerhoff  of Medicine
None
None
None
None
None
None
Carl E. Orringer
University of Miami, Soffer Clinical
Research Center-Associate Professor
None
None
None
None
None
None
Carmen Peralta
University of California, San Francisco-
Associate Professor of Medicine; Kidney
Health Research Collaborative-Executive
Director
None
None
None
None
None
None
(Continued )

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June 18/25, 2019
Circulation. 2019;139:e1082-e1143. DOI: 10.1161/CIR.0000000000000625
e1140
CLINICAL STATEMENTS
AND GUIDELINES
Grundy et al
2018 Cholesterol Clinical Practice Guidelines

Appendix 1. Continued
Committee
Member
Employment
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Beneft
Expert
Witness
Joseph Saseen
University of Colorado, Anschutz
Medical Campus-Professor and Vice
Chair, Department of Clinical Pharmacy;
Professor, Department of Family
Medicine
None
None
None
None
None
None
Sidney C. Smith, Jr
University of North Carolina, Chapel
Hill-Professor of Medicine
None
None
None
None
None
None
Laurence S.
Sperling
Emory University, Rollins School of
Public Health-Professor of Medicine,
Cardiology; Professor of Global Health
None
None
None
None
None
None
Salim S. Virani
Baylor College of Medicine-Professor,
Section of Cardiovascular Research
and Director, Cardiology Fellowship
Training Program; Michael E. DeBakey
VA Medical Center-Staff Cardiologist
and Investigator, Health Policy, Quality
& Informatics Program, Center for
Innovations in Quality, Effectiveness and
Safety
None
None
None
None
None
None
Joseph Yeboah
Wake Forest Baptist Health-
, Internal Medicine,
Cardiovascular
None
None
None
None
None
None
This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These
relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development
process. The table does not necessarily refect relationships with industry at the time of publication. A person is deemed to have a signifcant interest in a business
if the interest represents ownership of >=5% of the voting stock or share of the business entity, or ownership of >=$5 000 of the fair market value of the business
entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with
no fnancial beneft are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC/
AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or
issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document or
makes a competing drug or device addressed in the document; or c) the person or a member of the person's household, has a reasonable potential for fnancial,
professional or other personal gain or loss as a result of the issues/content addressed in the document.
*The Cholesterol Guideline began in September 2016. Over the initial years of the CMS Open Payment System, understandably, there have been many
issues related to the accurate reporting of food and beverage payments. For this reason, the ACC and AHA have not considered these minor charges relevant
relationships with industry.
AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; AAPA, American Academy of Physician Assistants; ABC, Association of
Black Cardiologists; ACC, American College of Cardiology; ACPM, American College of Preventive Medicine; ADA, American Diabetes Association; AGS, American
Geriatrics Society; AHA, American Heart Association; APhA, American Pharmacists Association; ASPC, American Society for Preventive Cardiology; PCNA,
Preventive Cardiovascular Nurses Association; and VA, Veterans Affairs.

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2018 Cholesterol Clinical Practice Guidelines
Circulation. 2019;139:e1082-e1143. DOI: 10.1161/CIR.0000000000000625
June 18/25, 2019 e1141
CLINICAL STATEMENTS
AND GUIDELINES

Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive)-2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the
Management of Blood Cholesterol (August 2018)
Peer
Reviewer
Representation
Employment
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other Financial
Beneft
Expert Witness
Salary
Philip A. Ades
Offcial Reviewer-
AACVPR
University of Vermont
Medical Center-
Professor of Medicine
None
None
None
None
None
None
None
Karen P.
Alexander
Offcial Reviewer-
ACC Science and
Quality Committee
Duke University Medical
Center-Professor of
Medicine/Cardiology
None
None
None
-  GSK
-  NIH
None
None
None
Theresa M.
Beckie
Offcial Reviewer-
AACVPR
University of South
Florida-Professor and
Associate Dean of the
PhD Program
None
None
None
None
None
None
None
Kathy Berra
Offcial Reviewer-
PCNA
Stanford University
-  Omada Health
None
None
None
-  Council on Aspirin
for Health and
Prevention - a
committee of the
Altarum Institute
-  Preventive
Cardiovascular
Nurses Association
None
None
William T.
Cefalu
Offcial Reviewer-
ADA
American Diabetes
Association-Chief
Scientifc, Medical and
Mission Offcer
None
None
None
None
None
None
None
Mary Ann
Champagne
Offcial Peer
Reviewer-PCNA
Stanford Hospital
and Clinics-Clinical
Nurse Specialist and
Coordinator
None
None
None
None
None
None
None
Joaquin
Cigarroa
Offcial Reviewer-
ACC/AHA Task Force
on Clinical Practice
Guidelines
Oregon Health and
Science University-
Clinical Professor of
Medicine
None
None
None
None
None
None
None
Stephen R.
Daniels
Offcial Reviewer-
AAP
University of Colorado
School of Medicine-
Professor and Chair,
Department of Pediatrics;
Children's Hospital
Colorado-Pediatrician
in-Chief and L. Joseph
Butterfeld Chair in
Pediatrics
-  Sanof-Aventis
None
None
None
-  Novo Nordisk Inc.
None
None
Dave Dixon
Offcial Reviewer-
NLA
Virginia Commonwealth
University School of
Pharmacy-Associate
Professor and Vice-Chair
for Clinical Services
None
None
None
None
None
None
None
Earl W.
Ferguson
Offcial Reviewer-
ACPM
Ridgecrest Regional
Hospital-Independent
Consultant
None
None
-  Bakersfeld
Heart Hospital
None
-  Growth Creators
Inc./Radekal/
Pertexa
-  California Health
Information
Partnership
and Services
Organization
None
None
Edward A.
Gill, Jr
Offcial Reviewer-
NLA
University of Colorado
Cardiology Division-
Professor of Clinic
Practice, Medicine-
Cardiology
None
None
None
None
None
None
-  Acute
Coronary
Syndrome
- 2007
Tyler J.
Gluckman
Offcial Reviewer-
ACC Board of
Governors
Providence St. Vincent
Heart Clinic-Medical
Director
-  Boehringer
Ingelheim
Pharmaceuticals
None
None
None
None
None
None
Rita Kalyani
Offcial Reviewer-
ADA
Johns Hopkins School
of Medicine-Associate
Professor of Medicine
None
None
None
None
None
None
None
Norma M.
Keller
Offcial Reviewer-
ACC Board of
Governors
New York University
Medical Center-Chief
of Cardiology
None
None
None
None
None
None
None
Amit Khera
Offcial Reviewer-
ASPC
University of Texas
Southwestern Medical
Center- of Medicine
None
None
None
None
None
None
None
(Continued )

Page 61
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Circulation. 2019;139:e1082-e1143. DOI: 10.1161/CIR.0000000000000625
e1142
CLINICAL STATEMENTS
AND GUIDELINES
Grundy et al
2018 Cholesterol Clinical Practice Guidelines

Appendix 2. Continued
Peer
Reviewer
Representation
Employment
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other Financial
Beneft
Expert Witness
Salary
Carol
Kirkpatrick
Offcial Reviewer-
NLA
Idaho State University-
Wellness Center Director/
Clinical Associate
Professor Kasiska Division
of Health Sciences
-  National Lipid
Association
None
None
None
None
None
None
G. B. John
Mancini
Offcial Reviewer-
ACC Board of
Governors
Vancouver Hospital
Research Pavilion-
Professor of Medicine
-  Amgen
-  Bayer
-  Boehringer
Ingelheim
Pharmaceuticals,
Inc
-  Eli Lilly and
Company
-  Esperion
-  Merck
-  Pfzer
-  Regeneron
-  Sanof-aventis/
Regeneron
-  Servier
None
None
None
None
None
None
Laxmi S.
Mehta
Offcial Reviewer-
ACC Science and
Quality Committee
Ohio State University-
Professor of Medicine;
Section Director of
Preventative Cardiology
and Women's
Cardiovascular Health
None
None
None
None
-  AHA
None
None
David
Montgomery
Offcial Reviewer-
ABC
Piedmont Heart
Institute-Cardiologist
None
None
None
None
None
None
None
Michelle
Odden
Offcial Reviewer-
AGS
Oregon State
University-Associate
Professor
None
None
None
None
None
None
None
Daniel J. Rader
Offcial Reviewer-
AHA
Cooper-McClure-
Professor of Medicine;
University of Pennsylvania
School of Medicine-
Director, Preventive
Cardiovascular Medicine
-  Alnylam*
-  Novartis*
-  Pfzer*
-  DalCor
-  MedImmune,
Inc
None
-  Staten Bio*
-  VascularStrategies*
None
None
None
None
Michael W.
Rich
Offcial Reviewer-
AGS
Washington University
School of Medicine-
Professor of Medicine
None
None
None
None
None
None
None
Mirvat A.
Alasnag
Content Reviewer-
ACC Early Career
Member Section
King Fahd Armed
Forces Hospital, Jeddah
KSA-Interventional
Cardiologist
None
None
None
None
None
None
None
Kim K. Birtcher
Content Reviewer-
ACC/AHA Task Force
on Clinical Practice
Guidelines
University of Houston
College of Pharmacy-
Clinical Professor
-  Jones & Bartlett
Learning
None
None
None
-  Accreditation
Council for Clinical
Lipidology
None
Conrad B.
Blum
Content Reviewer-
ACC/AHA
Medicine at Columbia
University Medical
Center-Professor
None
None
None
None
-  ACC-AHA
None
None
Bernard Dennis
Content Reviewer-
ACC/AHA Lay
Reviewer
Dennis Associates, LLC
None
None
None
None
None
None
None
Henry
Ginsberg
Content Reviewer-
AHA
Columbia University,
Irving-Professor of
Medicine
-  Merck
-  Resverlogix
-  Sanof-
Regeneron
-  Amgen
-  Akcea
-  Kowa
-  Janssen
-  Esperion
None
None
None
None
None
None
Ira Goldberg
Content Reviewer-
AHA
NYU Division of
Endocrinology, Diabetes,
and Metabolism-
Director
-  Akcea*
-  Amgen
-  Arrowhead
-  Intarcia
-  Merck
-  Regeneron
None
None
None
None
None
None
Jose A. Joglar
Content Reviewer-
ACC/AHA Task Force
on Clinical Practice
Guidelines
UT Southwestern
Medical Center
University-Professor of
Medicine
None
None
None
None
None
None
None
(Continued )

Page 62
Grundy et al
2018 Cholesterol Clinical Practice Guidelines
Circulation. 2019;139:e1082-e1143. DOI: 10.1161/CIR.0000000000000625
June 18/25, 2019 e1143
CLINICAL STATEMENTS
AND GUIDELINES

Appendix 2. Continued
Peer
Reviewer
Representation
Employment
Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other Financial
Beneft
Expert Witness
Salary
Glenn N.
Levine
Content Reviewer-
ACC/AHA Task Force
on Clinical Practice
Guidelines
Baylor College of
Medicine-Professor
of Medicine; Michael
E. DeBakey Medical
Center-Director, Cardiac
Care Unit
None
None
None
None
None
-  Defendant,
Out-of-hospital
cardiopulmonary
arrest, 2017*
None
Daniel Levy
Content Reviewer-
ACC/AHA
Center for Population
Studies-Director;
Journal of the
American Society of
Hypertension-Editor
in-Chief
None
None
None
None
None
None
None
Theodore
Mazzone
Content Reviewer-
ACC/AHA
NorthShore University
Health System-
Chairman, Department
of Medicine
None
None
None
None
None
None
None
Patrick E.
McBride
Content Reviewer-
ACC/AHA
University of Wisconsin
School of Medicine and
Public Health-Professor
Emeritus, Departments of
Medicine (Cardiovascular
Medicine) and Family
Medicine
None
None
-  Health
Decisions, Inc
None
None
None
None
Karen J.
McConnell
Content Reviewer-
APhA
Catholic Health
Initiatives-System
Director of Clinical
Pharmacy Services
None
None
None
None
None
None
None
Pamela B.
Morris
Content Reviewer-
ACC Prevention
of Cardiovascular
Disease Member
Section
The Medical University
of South Carolina-
Professor of Medicine,
Director of Preventative
Cardiology
-  Amgen
-  Esperion
-  Sanof
Regeneron
None
None
None
None
None
None
Nathalie Pamir
Content Reviewer-
AHA Scientifc
Council
Oregon Health and
Science University-

None
None
None
None
None
None
None
Janelle F.
Ruisinger
Content Reviewer-
APhA
The University of Kansas
School of Pharmacy,
Department of Pharmacy
Practice-Clinical
Pharmacist; KUMC
Atherosclerosis and
LDL-Apheresis Center-
Clinical Associate
Professor
None
None
None
-  Amgen
-  Regeneron
-  Sanof-
Aventis
-  American Society
of Health System
Pharmacists
None
None
Joshua
Schulman-
Marcus
Content Reviewer-
ACC Early Career
Member Section
Albany Medical Center-
 of
Medicine
None
None
None
None
None
None
None
Michael D.
Shapiro
Content Reviewer-
ACC Prevention
of Cardiovascular
Disease Member
Section
Oregon Health & Science
University-Associate
Professor of Medicine
and Radiology
-  Akcea
-  Amgen
-  Kastle*
-  Novartis
Corporation
-  Regeneron
None
None
-  Akcea
-  Amarin
-  Amgen
None
None
None
Susan Shero
Content Reviewer-
ACC/AHA
NIHNHLBI-Public Health
Advisor
None
None
None
None
None
None
None
James L.
Young II
Content Reviewer-
AHA
Beaumont Health-
Patient/Family Liaison
None
None
None
None
None
None
None
This table represents all relationships of reviewers with industry and other entities that were reported at the time of peer review, including those not deemed to be relevant to this document, at the time this
document was under review. The table does not necessarily refect relationships with industry at the time of publication. A person is deemed to have a signifcant interest in a business if the interest represents
ownership of >=5% of the voting stock or share of the business entity, or ownership of >=$5000 of the fair market value of the business entity; or if funds received by the person from the business entity
exceed 5% of the person's gross income for the previous year. Relationships that exist with no fnancial beneft are also included for the purpose of transparency. Relationships in this table are modest unless
otherwise noted. Please refer to http://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with-industry-policy for defnitions of disclosure categories or additional information
about the ACC/AHA Disclosure Policy for Writing Committees.
*Signifcant relationship.
No fnancial beneft.
AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; AAPA, American Academy of Physician Assistants; ABC, Association of Black Cardiologists; ACC, American
College of Cardiology; ACPM, American College of Preventive Medicine; ADA, American Diabetes Association; AGS, American Geriatrics Society; AHA, American Heart Association; APhA, American
Pharmacists Association; ASPC, American Society for Preventive Cardiology; GSK, GlaskoSmithKline; KSA, Kingdom of Saudi Arabia; KUMC, University of Kansas Medical Center; LDL, low-density lipoprotein;
NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institutes of Health; NLA, National Lipid Association; NYU, New York University; PCNA, Preventive Cardiovascular Nurses Association; and UT,
University of Texas.