Contemporary Reviews in Cardiovascular Medicine

Recent Update to the US Cholesterol Treatment Guidelines

A Comparison With International Guidelines
Matthew Nayor, MD; Ramachandran S. Vasan, MD

AbstractThe 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guideline advocated
several changes from the previous Adult Treatment Panel III guidelines. Assuming full implementation, the 2013 ACC/AHA
guideline would identify 13 million Americans as newly eligible for consideration of statin therapy. Three features of the
2013 ACC/AHA guideline primarily responsible for these differences are the specific risk assessment tool endorsed, the
risk threshold considered sufficient to warrant primary prevention statin therapy, and the decision not to include cholesterol
treatment targets. There is no consensus among international guidelines on the optimal approach to these 3 components. The
2013 ACC/AHA guideline recommends assessing absolute risk with the Pooled Cohort equations, which were developed
to improve on previous risk assessment models by including stroke as an outcome and by broadening racial and geographic
diversity. Each of the leading international guidelines recommends a different equation for absolute risk assessment. The 2013
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ACC/AHA guideline advises consideration of statin therapy for an estimated 10-year risk of atherosclerotic vascular disease
of 7.5%, which is lower than the thresholds recommended by other leading international guidelines. Lastly, the 2013 ACC/
AHA guideline does not endorse a treat-to-target strategy but instead specifies the appropriate intensity of statin for each
risk category. This approach is shared by the National Institute for Health and Care Excellence guidelines but differs from
other international guidelines. In this review, we summarize the 2013 ACC/AHA cholesterol guideline recommendations
and compare them with recommendations from Adult Treatment Panel III and other leading international guidelines.
(Circulation. 2016;133:1795-1806. DOI: 10.1161/CIRCULATIONAHA.116.021407.)
Key Words:cardiovascular diseases cholesterol guideline [publication type] prevention and control

D espite reductions in the mortality rate for cardiovascular

disease (CVD) among high- and middle-income countries
during the past 2 decades, approximately one third of global
deaths are still attributable to ischemic heart disease and stroke.1
These conditions also account for a large proportion of disabil-
ity and global healthcare costs.2,3 Elevated blood cholesterol is
among the most prevalent modifiable cardiovascular risk factors,
with medical therapies proven to reduce both CVD incidence
and related mortality.410 Therefore, clinical practice guidelines
addressing the treatment of blood cholesterol have a tremen-
dous potential impact on population health and related health-
care costs. The most recent US guidelines on the treatment of
blood cholesterol11 contain important changes from the previ-
ous version.12,13 In this review, we aim to summarize the rec-
ommendations from the most recent US cholesterol guideline,
highlighting specific changes from the previous version, and in
parallel compare it with other leading international guidelines.
Guidelines for the Treatment of Blood Cholesterol
Clinical Vignette
To demonstrate differences between the various guidelines,
we refer to a representative patient (Figure): Consider a
60-year-old nonsmoking white man without established CVD
or diabetes mellitus with no family history of premature CVD
who currently takes no medications. He is 69 in (175 cm) tall
and weighs 180 lb (81.6 kg); his body mass index is 26.6 kg/
m2; his blood pressure is 144/86 mmHg; and his fasting lipid
profile reveals a total serum cholesterol of 195 mg/dL, low-
density lipoprotein (LDL) cholesterol (LDL-C) of 125 mg/
dL, high-density lipoprotein cholesterol (HDL-C) of 50 mg/
dL, and triglycerides of 100 mg/dL (to convert from mg/dL to
mmol/L, multiply LDL-C or HDL-C by 0.0259 and multiply
triglycerides by 0.0113).
2013 American College of Cardiology/
American Heart Association Guideline
Methodology
The 2013 American College of Cardiology/American Heart
Association Guideline on the Treatment of Blood Cholesterol
to Reduce Atherosclerotic Cardiovascular Risk in Adults11
(2013 ACC/AHA guideline) was commissioned to reflect new
evidence since the previous Adult Treatment Panel III (ATP
III) guidelines were last updated in 2004.12,13 Whereas previ-
ous cholesterol guidelines targeted the prevention of coronary

From Framingham Heart Study, Framingham, MA (M.N., R.S.V.); Brigham and Womens Hospital, Division of Cardiovascular Medicine, Boston, MA
(M.N.); Sections of Preventive Medicine and Cardiology, Boston University School of Medicine, MA (R.S.V.); and Department of Epidemiology, Boston
University School of Public Health, MA (R.S.V.).
Correspondence to Matthew Nayor, MD, Cardiovascular Division, Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115. E-mail
mnayor@partners.org
2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.116.021407

1795
 1796CirculationMay 3, 2016
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Figure. Clinical vignette and recommendations according to different international guidelines. ACC indicates American College of
Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; ATP III, Adult Treatment Panel III; BP,
blood pressure; CCS, Canadian Cardiovascular Society; CHD, coronary heart disease; CVD, cardiovascular disease; EAS, European
Atherosclerosis Society; ESC, European Society of Cardiology; HDL-C, high-density lipoprotein cholesterol; LDL-C, low density lipopro-
tein cholesterol; and NICE, National Institute for Health and Care Excellence.

heart disease (CHD), the 2013 ACC/AHA guideline expanded
the focus to atherosclerotic CVD (ASCVD), including CHD,
stroke, and peripheral arterial disease. The 2013 ACC/AHA
task force used a new approach to assess available evidence,
focusing on randomized, controlled trials and systematic
reviews and meta-analyses of randomized, controlled trials.
Furthermore, the new guideline differed from the previous
iterations in its intended scope. Whereas the ATP III guide-
lines included a comprehensive topical review and recommen-
dations for laboratory evaluation, clinical diagnosis, lifestyle
interventions, and drug therapy, the 2013 ACC/AHA guide-
line focused on answering 3 critical questions: (1) What is
the evidence for LDL-C and nonHDL-C goals in secondary
prevention of ASCVD? (2) What is the evidence for LDL-C
and nonHDL-C goals in primary prevention of ASCVD?
(3) What are the effectiveness and safety of lipid-modifying
drugs in the primary and secondary prevention of ASCVD?11
An independent contractor selected the relevant studies to be
reviewed for each critical question according to prespecified
criteria. This methodology was designed to reduce bias and to
ensure that lower-quality studies were not considered when
the recommendations were formulated.
Risk Assessment Model
A new tool for global risk assessment was introduced with
the 2013 ACC/AHA guideline.11 The previous guidelines rec-
ommended using a modified Framingham Risk Score (FRS)
to estimate the 10-year risk of myocardial infarction or CHD
death. Criticisms of this model included the absence of stroke
as an outcome and a lack of racial, ethnic, and geographic
diversity in the derivation population. In response, the Pooled
Cohort equations were derived with data from 4 National
Heart, Lung, and Blood Institutesponsored cohort studies
the Atherosclerosis Risk in Communities (ARIC) study, the
Cardiovascular Health Study (CHS), the Coronary Artery
Risk Development in Young Adults (CARDIA) study, and the
Framingham Heart Study (FHS; including original and off-
spring cohorts)with adjudicated clinical outcomes, includ-
ing myocardial infarction, CHD death, and fatal or nonfatal
stroke.14 The risk factors meeting the criteria for inclusion in
the multivariable model were age, sex, total cholesterol, HDL-
C, systolic blood pressure, antihypertensive treatment status,
diabetes mellitus, and current smoking status. Of these vari-
ables, only diabetes mellitus was not included in the modified
FRS endorsed by the ATP III guidelines. Different multivari-
able models were constructed for white and black individuals,
and caution was recommended when these equations were
applied to other races and to adults outside the age range of
40 to 79 years.
Treatment Recommendations
The 2013 ACC/AHA guideline recommended treatment with
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors
(statins) for 4 categories of individuals: (1) secondary pre-
vention for those with established ASCVD, (2) primary pre-
vention of ASCVD for those with LDL-C 190 mg/dL, (3)
primary prevention of ASCVD for individuals with diabetes
mellitus and LDL-C of 70 to 189 mg/dL, and (4) primary pre-
vention of ASCVD for those without diabetes mellitus, with
LDL of 70 to 189 mg/dL, but with an estimated 10-year abso-
lute risk of 7.5% as assessed by the Pooled Cohort equa-
tions. For this fourth group especially, the guideline authors
 Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1797
emphasized the importance of shared decision making based
on a detailed risk discussion between patient and clinician
before the initiation of statin therapy.15 This clinician-patient
discussion should include an assessment of the potential ben-
efit, possible adverse effects and drug-drug interactions, life-
style changes, management of other risk factors, and of course
patient preferences. Additionally, other factors that might
affect net risk reclassification could be used to further inform
the treatment decision; these include LDL-C 160 mg/dL or
evidence of genetic dyslipidemia, elevated lifetime risk, fam-
ily history of premature CVD, blood levels of high-sensitivity
C-reactive protein 2.0 mg/L, ankle-brachial index <0.9, or
abnormal coronary artery calcium score (300 Agatston units
or 75th percentile for age, sex, and ethnicity). Individuals at
intermediate risk (10-year absolute risk of 5%7.4%) or low
risk (10-year absolute risk <5%) could also be considered for
statin therapy on the basis of patient preferences or perceived
benefit based on additional factors such as those listed above.
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Instead of setting specific LDL-C targets, the 2013 ACC/
AHA guideline essentially suggested a fixed dose (or inten-
sity) of statin for each risk category, with intended LDL-C
reductions of 30% to 49% and 50% for moderate- and high-
intensity statins, respectively. The authors also suggested that
nonstatin medications could be considered for those at high
risk (secondary prevention, diabetes mellitus, LDL-C 190
mg/dL) if they are intolerant of the recommended dose of
statin or have an inadequate response to statins. Although spe-
cific LDL-C targets were not endorsed, the 2013 ACC/AHA
guideline recommended monitoring of the plasma lipid levels
to ensure adherence, therapeutic response, and safety.
In comparison, the ATP III guidelines recommended a
treat-to-target strategy with specific LDL-C goals for each
risk group. For primary prevention, the LDL-C goal was set
at <100 mg/dL for high-risk individuals (10-year CHD risk
>20%), <130 mg/dL for those at intermediate risk (10-year
risk CHD risk, 10%20%), and <160 mg/dL for low-risk
individuals (10-year CHD risk <10%). The LDL-C goal for
secondary prevention or primary prevention of CVD in those
with diabetes mellitus was <100 mg/dL, with the option to
target <70 mg/dL for those at highest risk of CVD.12,13
In summary, the most important differences between the
2013 ACC/AHA guideline and the ATP III guidelines are the
introduction of the Pooled Cohort equations, the elimination
of LDL-C treatment targets, and the lowering of the threshold
at which statins should be considered to an estimated 10-year
absolute risk of 7.5%. The differences between these 2 docu-
ments are summarized in Table1. To provide further context
for the 2013 ACC/AHA guideline, we next compare its rec-
ommendations with those from other leading international
guidelines, as outlined in Table2.
Clinical Vignette
With the Pooled Cohort equations, the patient in our clinical
vignette would have an estimated 10-year absolute ASCVD
risk of 10.3%, and moderate- to high-intensity statin ther-
apy could be considered after a clinician-patient discussion
of potential risk reduction, adverse effects, drug-drug inter-
actions, and patient preferences. With the modified FRS
endorsed by the ATP III guidelines, on the other hand, he
would be considered at intermediate risk on the basis of an
estimated 10-year absolute risk of CHD of 10%. Hence, his
LDL-C target would be <130 mg/dL, and given his current
LDL-C of 125 mg/dL, he would not receive statin therapy.
Notably, a white man was used for our representative clini-
cal vignette. The difference in estimated risk between the Pooled
Cohort equations and the FRS would be more pronounced if
a black woman, for example, had the same risk factor profile.
With the Pooled Cohort equations, she would have an estimated
10-year ASCVD risk of 7.4%, which is considerably higher than
the 2% 10-year CHD risk estimated by the FRS.
2011 European Society of Cardiology/
European Atherosclerosis Society Guidelines
Methodology
The European Society of Cardiology/European Atherosclerosis
Society Guidelines for the Management of Dyslipidaemias16
(2011 ESC/EAS guidelines) are a comprehensive document
addressing cardiovascular risk assessment, laboratory evalua-
tion, lifestyle modifications, drug treatment, and the approach
to specific clinical settings such as familial dyslipidemias. The
ESC/EAS task force based its findings on a comprehensive
review of the literature in which greater confidence was placed
in the results of randomized, controlled trials but was inclu-
sive of all study designs.
Risk Assessment Model
Similar to the 2013 ACC/AHA guideline, the 2011 ESC/EAS
guidelines supported the routine use of global cardiovascu-
lar risk assessment for all adults without established CVD but
endorsed the use of the Systemic Coronary Risk Evaluation
(SCORE) risk assessment tool. The SCORE tool, derived
by pooling data from cohort studies with participants in 12
European countries, is designed to estimate the 10-year risk
of fatal CVD event.19 The decision to include only fatal out-
come events was based on the assessment that fatal events are
more easily calibrated in different populations and are less
likely than nonfatal events to be affected by local geographic
variations in diagnosis and treatment.19 The total CVD event
rate (including nonfatal events) has been shown to be 3-fold
higher than the fatal CVD event rate.16 Variables included in
the SCORE risk model include age, sex, systolic blood pres-
sure, total cholesterol, and smoking status, and separate mod-
els are used for low- and high-risk European countries.
Treatment Recommendations
According to the 2011 ESC/EAS guidelines, patients are
considered to be very high risk for documented CVD, type 2
diabetes mellitus, type 1 diabetes mellitus with target organ
damage, moderate to severe chronic kidney disease (CKD), or
estimated 10-year absolute risk of fatal CVD 10%. High-risk
individuals are those with a 10-year risk of fatal CVD of 5%
to 9.9% or marked elevations in risk factors such as familial
dyslipidemia or severe hypertension. Moderate risk is defined
as a 10-year risk of fatal CVD of 1% to 4.9%, and low risk is
defined as an estimated 10-year risk of fatal CVD event <1%.
Extrapolating from clinical trials, the task force recommended
LDL-C goals of approximately <70 mg/dL (1.8 mmol/L) for
 1798CirculationMay 3, 2016

Table 1. Comparison of 2013 ACC/AHA and ATP III Guidelines for the Treatment of Blood Cholesterol
Criteria 2013 ACC/AHA Guideline11
Focus of primary prevention ASCVD, including CHD, stroke, and peripheral arterial disease
Guideline scope Limited to 3 critical questions: evidence for cholesterol goals in
secondary prevention, evidence for cholesterol goals in primary
prevention, and effectiveness and safety of lipid-modifying drugs
Evidence considered Randomized, controlled trials and meta-analyses of randomized,
controlled trials
Risk assessment tool Pooled Cohort risk equations:
End points: CHD death, nonfatal MI, fatal or nonfatal stroke
Derivation sample: pooled data from 4 cohort studies
Predictors selected in the multivariable model: age, sex, total
cholesterol, HDL-C, systolic blood pressure, antihypertensive
treatment status, diabetes mellitus, and current smoking status
Additional considerations: separate models created for men and
women and for whites and blacks
Cholesterol treatment targets endorsed No
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2001 ATP III Guidelines12 With 2004 Update13
CHD
Comprehensive document, including literature
review, diagnosis and evaluation, treatment,
lifestyle changes, and special clinical settings
Inclusive systematic review
Modified FRS:
End points: CHD death, nonfatal MI
Derivation sample: mostly white population of
European descent
Predictors selected in the multivariable model:
age, sex, total cholesterol, HDL-C, systolic blood
pressure, antihypertensive treatment status, and
current smoking status
Yes

Lipid-lowering therapy for primary LDL-C 190 mg/dL: high-intensity statin LDL-C 190 mg/dL
prevention in those without diabetes LDL-C 70189 mg/dL and: 2 clinical risk factors and:
mellitus 10-y risk 7.5%: high-intensity statin after clinician-patient High risk (10-y risk >20%) and LDL-C 100 mg/
discussion dL (70 mg/dL optional): statin
10-y risk <7.5%: can consider moderate-intensity statin after Intermediate risk (10-y risk, 10%20%) and
consideration other factors* and based on a clinician-patient LDL-C 130 mg/dL (100 mg/dL optional): statin
discussion Low risk (10-y risk <10%) and LDL-C 160 mg/
dL: may consider statin
Lipid-lowering therapy for primary LDL-C 70 mg/dL and: LDL-C 100 mg/dL: statin
prevention in those with diabetes 10-y risk 7.5%: high-intensity statin LDL-C 70 mg/dL with high risk features
mellitus 10-y risk <7.5%: moderate-intensity statin (optional): statin
Lipid-lowering therapy for secondary High-intensity statin If LDL-C 100 mg/dL (70 mg/dL optional): statin
prevention
NonLDL-C targets Not discussed HDL-C and triglyceride targets discussed in detail
Specific recommendations for the Pooled Cohort risk equations not validated in age >79 y Modified FRS not validated in age 65 y
elderly Consider lower-intensity statin if age >75 y Clinical judgment recommended in older adults
ACC/AHA indicates American College of Cardiology/American Heart Association; ASCVD, atherosclerotic cardiovascular disease; ATP III, Adult Treatment Panel III;
CHD, coronary heart disease; FRS, Framingham Risk Score; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; and MI, myocardial
infarction.
*Other factors to consider include LDL-C 160 mg/dL, family history, high sensitivity C-reactive protein, coronary artery calcium score, ankle-brachial index, and
lifetime risk.
Clinical risk factors include male age 45 y, female age 55 y, family history of premature CHD, current smoking, hypertension (140/90 mmHg or on
antihypertensive medications), and high-density lipoprotein <40 mg/d.

very high risk, <100 mg/dL (2.5 mmol/L) for high risk, <115
mg/dL (3.0 mmol/L) for moderate risk, and <190 mg/dL (4.9
mmol/L) for low risk. Therefore, the 2011 ESC/EAS guide-
lines differ from the 2013 ACC/AHA guideline in the choice
of risk assessment model, the estimated 10-year risk consid-
ered sufficient to warrant medical treatment, and the contin-
ued endorsement of specific LDL-C targets to guide therapy.
Clinical Vignette
According to the SCORE risk assessment tool, our patient
has a 10-year estimated risk of CVD mortality of 5% if he
lives in a high-risk European country and would be consid-
ered at high risk. If he lives in a low-risk country, however,
his 10-year estimated risk of CVD death would be 3%, and
he therefore would be considered at moderate risk. Regardless
of his country of residence, statin treatment would be recom-
mended, given the LDL-C targets of <100 mg/dL for high-risk
and <115 mg/dL for moderate-risk individuals.
2014 National Institute for Health
and Care Excellence Guidelines
Methodology
The guidelines for lipid modification from the National
Institute for Health and Care Excellence (NICE) in England
were last updated in 2014.17 The NICE guidelines are similar
in scope to the 2013 ACC/AHA guideline, with recommenda-
tions for the primary and secondary prevention of CVD. Of
the international guidelines reviewed, the NICE guidelines are
noteworthy for the specificity of the drug recommendations
provided and for the extent to which cost-effectiveness analy-
ses are used to justify the recommendations.
Risk Assessment Model
The NICE guidelines support the use of the QRISK2 risk
assessment tool for global cardiovascular risk assessment in
all adults <84 years of age who are free of CVD. The QRISK2
 Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1799

Table 2. Comparison of International Guidelines for the Treatment of Blood Cholesterol

Criteria
Evidence considered
Risk assessment tool
End points
Derivation sample
Predictors selected in the
multivariable model
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2013 ACC/AHA Guideline11
Randomized, controlled trials
Pooled Cohort equations
CHD death, nonfatal MI, fatal
or nonfatal stroke
Pooled data from 4 cohorts
Age, sex, total cholesterol,
HDL-C, systolic blood
pressure, antihypertensive
treatment status, diabetes
mellitus, and smoking status
2011 ESC/EAS Guidelines16
Comprehensive literature
review
SCORE risk assessment tool
CHD death or fatal stroke
(total CVD events is 3-fold
higher than fatal event rate)
Pooled data from 12
European countries
Age, sex, total cholesterol,
systolic blood pressure, and
smoking status
(separate models for high-
2014 NICE Guidelines17
Comprehensive literature
review
QRISK2 risk assessment tool
CHD death, CHD (MI or
angina), stroke, or transient
ischemic attack
British population, updated
annually
Age, sex, total cholesterol,
HDL-C, systolic blood
pressure, hypertension
treatment status, diabetes
mellitus, smoking status,
2012 CCS Guidelines18
Comprehensive literature
review
FRS for total CVD
CHD death, MI, coronary
insufficiency, angina,
ischemic or hemorrhagic
stroke, transient ischemic
attack, peripheral artery
disease, heart failure
Mostly white population of
European descent
Age, sex, total cholesterol,
HDL-C, systolic blood
pressure, antihypertensive
treatment status, diabetes
mellitus, and smoking status

and low-risk countries)

(separate models created for ethnicity, family history
whites and blacks) of CHD, body mass index,
socioeconomic deprivation,
rheumatoid arthritis, CKD,
and atrial fibrillation
Cholesterol treatment targets No Yes (LDL-C) No Yes (LDL-C)
endorsed Consider ApoB or nonHDL-C Consider ApoB and non
as alternative target HDL-C as alternative target
Lipid-lowering therapy for LDL-C 190 mg/dL LDL-C 190 mg/dL 10-y risk 10% or CKD LDL-C 190 mg/dL
primary prevention in those LDL-C 70189 mg/dL and: LDL-C <190 mg/dL and: LDL-C <190 mg/dL and 10-y
without diabetes mellitus risk 5%9% (optional)
10-y risk 7.5% after 10-y risk 10%
clinician-patient discussion Moderate to severe CKD LDL-C 130 mg/dL and 10-y
10-y risk <7.5% after risk 10%19%
LDL-C 100 mg/dL and:
consideration of other LDL-C 75 mg/dL and:
10-y risk 5%9.9%
factors and based on 10-y risk 20%
clinician-patient discussion Severe risk factors
CKD or proteinuria
LDL-C 115 mg/dL and
High-risk hypertension*
10-y risk 1%4.9%
Lipid-lowering therapy for LDL-C 70 mg/dL Type 2 diabetes mellitus and Type 2 diabetes mellitus and Age 40 or <40 y and
primary prevention in those LDL-C 100 mg/dL 10-y risk 10% duration of disease >15 y, or
with diabetes mellitus High-risk type 2 diabetes Type 1 diabetes mellitus age >30 y with microvascular
mellitus and LDL-C 70 and age >40 y, duration of complications
mg/dL disease >10 y, nephropathy,
Type 1 diabetes mellitus and or CVD risk factors
target organ damage
CKD considered a high-risk No Yes Yes Yes
feature
Specific recommendations for Pooled Cohort risk equations SCORE validated for ages QRISK2 is calibrated to age FRS to be used in age 75 y
the elderly not validated for age >79 y 4065 y 84 y Clinical judgment urged in
Consider lower-intensity Clinician judgment urged in those >75 y
statin elderly
Additional considerations for Lifetime risk NonLDL-C targets NonLDL-C targets Cardiovascular age and
risk assessment nonLDL-C targets
ACC/AHA indicates American College of Cardiology/American Heart Association; ApoB, apolipoprotein B; CCS, Canadian Cardiovascular Society; CHD, coronary heart
disease; CKD, chronic kidney disease; CVD, cardiovascular disease; ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; FRS, Framingham Risk
Score; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NICE, National Institute for Health and Care
Excellence; and SCORE, Systemic Coronary Risk Evaluation.
*High-risk hypertension is defined as hypertension plus 3 of the following risk factors: male, age >55 years, smoking, total cholesterol/HDL-C ratio >6, left ventricular
hypertrophy, family history of premature CVD, ECG abnormalities, or microalbuminuria.
High-risk type 2 diabetes mellitus is defined as diabetes mellitus plus 1 of the following risk factors: established CVD, CKD, age >40 years, and 1 or more
cardiovascular risk factor or target organ damage.
 1800CirculationMay 3, 2016

model estimates the 10-year absolute risk of CHD (angina or
myocardial infarction), stroke, or transient ischemic attack; is
specifically calibrated to the British population; and is updated
annually. Compared with the Pooled Cohort equations and
SCORE risk assessment tool, the QRISK2 multivariable model
includes additional risk factors such as ethnicity, family his-
tory of premature CHD, socioeconomic deprivation, body mass
index, rheumatoid arthritis, CKD, and atrial fibrillation (in addi-
tion to age, sex, systolic blood pressure, total cholesterol, HDL-
C, hypertension treatment status, diabetes mellitus, and smoking
status, which are included in the Pooled Cohort equations).20
Treatment Recommendations
Similar to the 2013 ACC/AHA guideline, the 2014 NICE
guidelines do not endorse a treat-to-target strategy. Instead,
statin therapy is recommended for primary prevention in indi-
viduals with type 2 diabetes mellitus or those without diabetes
mellitus but with an estimated 10-year absolute CVD risk of
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also recommended for those with diabetes mellitus and for
secondary prevention, with a goal of <70 mg/dL (1.8 mmol/L)
considered to be optional for those at highest risk.
Clinical Vignette
The patient in our clinical vignette has an estimated 10-year
risk of total CVD of 16.6% according to the FRS and would
be characterized as intermediate risk. The LDL-C target for
the intermediate-risk group is <130 mg/dL. Therefore, he
would not be recommended to receive statin therapy.
Comparison of International Guidelines
The 2013 ACC/AHA guideline differs substantially from its
previous version, the ATP III guidelines, and other leading
international guidelines. The effects of these changes were
illustrated by our representative clinical vignette, in which the
recommendations for initiating statin therapy for a 60-year-old
man with modest cardiometabolic risk factors varied accord-

10%. Statin therapy is also recommended for patients with
type 1 diabetes mellitus who are >40 years of age with a dis-
ease duration of >10 years or with evidence of target organ
damage. Atorvastatin 20 mg daily is recommended for pri-
mary prevention, and atorvastatin 80 mg daily is used for sec-
ondary prevention. In patients with CKD, 20 mg atorvastatin
is suggested for both primary and secondary prevention.
Clinical Vignette
The patient in our clinical vignette has an estimated 10-year
CVD risk of 10.4% with the QRISK2 model and would thus
meet the criteria for statin therapy as primary prevention.
2012 Canadian Cardiovascular
Society Guidelines
Methodology and Risk Assessment Model
The Canadian Cardiovascular Society (CCS) guidelines for
the diagnosis and treatment of dyslipidemia for the prevention
of CVD in adults were last updated in 2012 (2012 CCS guide-
lines).18 The 2012 CCS guidelines recommend using the FRS
for total CVD events to estimate the 10-year absolute risk.
These guidelines also suggest doubling the estimated absolute
risk for individuals with a family history of premature CVD
on the basis of evidence of a 2-fold increase in CVD risk for
FHS participants with a family history of premature CVD.21
The authors of the 2012 CCS guidelines advise considering
cardiovascular age in addition to estimated 10-year absolute
risk when discussing lipid-lowering treatment with patients.
Cardiovascular age and heart age may be easier concepts
for patients to understand and may thereby facilitate shared
decision making between patient and provider.22
Treatment Recommendations
The 2012 CCS guidelines endorse a treat-to-target strategy
with primary prevention LDL-C targets of <75 mg/dL (2.0
mmol/L) for high-risk patients (10-year absolute risk 20%,
CKD, or high-risk hypertension), <130 mg/dL (3.5 mmol/L)
for intermediate-risk individuals (10-year absolute risk, 10%
19%), and <190 mg/dL (5 mmol/L) for those at low risk (10-
year absolute risk <10%). A target LDL-C of <75 mg/dL is
ing to the guideline followed (Figure). The leading interna-
tional guidelines included in this review differ in 3 key areas:
the suggested risk assessment model (component risk factors
and outcome evaluated), the threshold of risk considered suf-
ficient to warrant initiating medical therapy, and the decision
of whether to use a treat-to-target strategy.
Predicted Impact of Changes Proposed
by the 2013 ACC/AHA Guideline
Dyslipidemia and cardiometabolic risk factors are highly
prevalent in the population; therefore, changes to cholesterol
treatment guidelines will affect the treatment recommenda-
tions for many people. Using data from the National Health
and Nutrition Examination Surveys (NHANES), Pencina and
colleagues demonstrated that 13 million American adults
would be newly eligible for statin therapy with full imple-
mentation of the 2013 ACC/AHA guideline.23 The increase in
statin eligibility was attributable primarily to a higher propor-
tion of individuals 60 to 75 years of age meeting criteria for
treatment, which grew from 47.8% with the ATP III guidelines
to 77.3% with the 2013 ACC/AHA guideline. The true impact
of the 2013 ACC/AHA guideline is likely to be overestimated
by these calculations, which assumed that all individuals in a
statin benefit group would be treated with statins and there-
fore did not consider the effect of a clinician-patient discus-
sion (emphasized by the new guidelines specifically) of the
risks and benefits of statin initiation. Nevertheless, the 2013
ACC/AHA guideline is predicted to result in a higher number
of statin-eligible individuals in the United States.
The overall impact of a larger proportion of the popula-
tion receiving statin therapy is uncertain. Although overtreat-
ment is a concern,24 several recent studies have suggested
that the 2013 ACC/AHA guideline aligns more closely than
the ATP III guidelines with coronary atherosclerotic burden,
as assessed by coronary artery calcium score and computed
tomography angiography.25,26 The features primarily responsi-
ble for the differences in statin allocation when the 2013 ACC/
AHA guideline is compared with the ATP III guidelines are
the risk assessment models used and the potential increase in
statin assignment to lower-risk primary prevention.
 Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1801
Absolute Risk Estimation: A
Comparative Critique
The Pooled Cohort equations were introduced alongside the
2013 ACC/AHA guideline with the goals of broadening eth-
nic and geographic diversity and incorporating stroke as an
outcome in the risk prediction model.14 Since their publica-
tion, several features of the Pooled Cohort equations have
been criticized, including potential overestimation of absolute
risk, dependence on chronological age, and derivation in older
cohorts with reduced performance in more contemporary
cohorts.
Absolute Risk Estimation
Overestimation of risk was first reported in the 2013 ACC/
AHA guideline on the assessment of cardiovascular risk, dur-
ing external validation with data from the more contemporary
Multi-Ethnic Study of Atherosclerosis (MESA) and Reasons
for Geographic and Racial Differences in Stroke (REGARDS)
Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017
cohorts, and with updated data from ARIC and FHS.14 Several
explanations for these findings were proposed. Foremost, a
follow-up of at least 12 years was required for the derivation
cohorts to accurately predict 10-year risk. Therefore, secular
trends in statin use, revascularization procedures, or treat-
ment of other risk factors such as hypertension and diabetes
mellitus may account for the lower rates of CVD observed in
more contemporary cohorts.2729 Underascertainment of clini-
cally relevant events in the validation cohorts may also explain
the apparent overestimation. In fact, when investigators used
Medicare claims data to improve outcome ascertainment for
the REGARDS study, they demonstrated improved perfor-
mance of the Pooled Cohort equations.28 However, concerns
about the Pooled Cohort equations remain. Overestimation has
repeatedly been demonstrated in several modern cohorts,24,30,31
and in at least the Womens Health Study, the overestimation
was not explained by differences in statin use, revascular-
izations, or underascertainment.27 Despite these findings, it
should be noted that the Womens Health Study was a primary
prevention trial composed of clinical trial volunteers.32 The
lower risk observed in this study might therefore be partially
attributable to a healthy volunteer effect.33
Although further investigation into the performance of
the Pooled Cohort equations may be warranted, it is worth
considering whether other existing risk prediction models
perform better. This question is underscored by the observa-
tion that each of the leading international guidelines endorses
a different risk assessment model. Unfortunately, systematic
comparisons between risk prediction models are rare, and
results are often conflicting, depending on the characteristics
of the populations studied.34 The FRS, for example, has been
shown to both overestimate and underestimate risk in different
populations.35
Model Performance Characteristics
Model calibration and discrimination are 2 features that can
be used to assess the performance of risk prediction models.
Calibration, estimated by the Hosmer-Lemeshow statistic, rep-
resents how well the predicted risk approximates the observed
risk. Discrimination, measured by the c statistic, refers to how
well the model distinguishes those who develop the disease
from those who do not.36 With data from the Rotterdam Study,
investigators compared the performance of the Pooled Cohort
equations, the modified FRS, and the SCORE risk assess-
ment tool and determined that calibration was similarly poor
among the 3 models, all of which significantly overestimated
the risk of first CVD event.24 Furthermore, discrimination was
modest (highest with the SCORE tool) among the 3 models
(c statistics ranging from 0.670.77).24 Similarly, investigators
from the MESA cohort evaluated the performance of 3 dif-
ferent FRSs, the Reynolds Risk Score, and the Pooled Cohort
equations.31 They found modest calibration for the 5 scores,
with superior discrimination when the Reynolds Risk Score
was used. Despite the differences demonstrated in the above
studies, there is little consensus on the optimal risk prediction
model.
Choice of Variables and Optimizing Models
The different risk prediction models endorsed by the inter-
national cholesterol guidelines vary little in terms of the risk
factors included as predictors, with the QRISK2 model being
noteworthy for incorporating additional variables. Future
consideration could be given to assessing the desirability,
appropriateness, and feasibility of establishing a more uni-
fied framework for estimating cardiovascular risk globally,
perhaps by developing an international CVD risk prediction
model. When data from international cohorts are combined,
geographic, racial, and ethnic diversity can be optimized. The
feasibility of this approach and the ability to calibrate a risk
score to different countries were recently demonstrated.37 Of
course, there are several important hurdles to pursuing this
approach globally. Primary among these is the lack of data
for certain geographic and ethnic groups. For example, the
so-called BRIC countries of Brazil, Russia, India, and China
represent 40% of the worlds population, but data on car-
diovascular risk assessment in these countries are limited.38
Furthermore, the degree to which individual risk assessment is
affected by local characteristics that are not easily evaluated or
integrated into risk prediction models is uncertain. These may
include factors such as local environment, diet, climate, air
pollution, built environment, cultural factors, availability of
health care, and genetic background. With the representative
patient in our clinical vignette, we observed important differ-
ences in the estimated risk using each of the 5 risk assess-
ment models. Although these differences could be partially
explained by specific model characteristics, the unique local
factors may further contribute to variations in the weighting of
variables, which could complicate direct comparison or har-
monization of the different risk assessment models.
The 3 most important features of a risk prediction model
are the covariates included, the outcomes modeled, and the
time horizon. Optimization of each of these features may help
further refine risk prediction techniques. As previously men-
tioned, most existing risk prediction models rely primarily on
age, sex, cholesterol, blood pressure, hypertensive treatment
status, diabetes mellitus, and smoking status. These individual
measurements do not account for variations in lifetime expo-
sure to risk factors. Because traditional cardiovascular risk
factors generally lead to atherosclerosis over decades, it is
 1802CirculationMay 3, 2016
reasonable to hypothesize that the duration of exposure may
be important. This approach is commonly used for cigarette
smoking, which is recorded in pack-years of exposure, and
there is evidence to support a similar approach with hyperten-
sion and dyslipidemia.3941 It is also notable that family history
of premature CHD is included in the QRISK2 model and the
modification of the FRS endorsed by the CCS but is not incor-
porated into the SCORE or Pooled Cohort equations models.
Because, as cited by the 2012 CCS guidelines, there are data
supporting a 2-fold increased risk in those with a family his-
tory of premature CVD,21 it is intriguing that this variable did
not meet the criteria for inclusion in certain models. Perhaps,
it is related to how family history is defined or measured in
the derivation cohorts. Although not included as a covariable
in the Pooled Cohort equations model, the 2013 ACC/AHA
guideline included family history of premature CVD as an
important factor that can be considered when a risk decision is
uncertain. In addition to improving how established risk fac-
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tors are measured, discovery of new risk predictors (eg, using
genomic data, biomarkers, and advanced imaging techniques)
is an area of active investigation.
The optimal outcomes to include in a CVD risk prediction
model remain uncertain. In particular, the inclusion of stroke
in the Pooled Cohort equations has been questioned. Although
CHD and myocardial infarction are almost exclusively caused
by atherosclerotic disease, stroke is a heterogeneous disorder
in which large-vessel atherosclerosis accounts for 40% of
the disease burden.4244 Because blood cholesterol is directly
related only to large-vessel atherosclerosis, using the same
risk factors to predict CHD and stroke may be overly sim-
plistic. In fact, low LDL-C has paradoxically been associated
with a higher risk of hemorrhagic stroke in some studies.45
Furthermore, it is well described that the incidence of stroke in
the United States varies widely by geographic region, giving
rise to the term stroke belt to refer to a grouping of 11 south-
eastern US states with age-adjusted stroke mortality rates that
are 10% higher than the national average.46 This area is not
well represented in the 4 National Heart, Lung, and Blood
Institute cohort studies used for the derivation of the Pooled
Cohort equations. Therefore, using these equations to estimate
the risk of stroke in the stroke belt will undoubtedly result in
underestimation. Lastly, stroke disproportionally affects the
elderly, with 17% of all stroke patients >85 years of age, an
age group that is underrepresented in the discovery cohorts.47
Therefore, including stroke as an outcome might reduce model
precision and could further contribute to increased weighting
of age in the risk prediction model.
Impact of Age on Absolute Risk Assessment
Indeed, the dramatic effect of age on estimated risk is an addi-
tional criticism of the Pooled Cohort equations, yet such age
effects are observed to some extent in all of the previously
mentioned risk prediction models. With the Pooled Cohort
equations, many older adults may exceed the 7.5% estimated
10-year ASCVD risk threshold even in the absence of smok-
ing, diabetes mellitus, hypertension, or dyslipidemia.48 This
feature is partially a result of the commonly used 10-year time
window for risk prediction. The absolute event rate increases
with age, as will the predicted risk. Therefore, approaches
that are independent of chronological age such as estimating
cardiovascular age or lifetime risk are appealing alternatives
because the primary prevention of ASCVD during the life
course, as opposed to during 10-year windows, is the ultimate
aim. Reflecting this concept, the Pooled Cohort equations pro-
vide an estimated lifetime risk for individuals 20 to 59 years
of age, and the 2012 CCS guidelines endorse the use of heart
age in clinical decision making. However, further research is
required to determine how best to apply these assessments in
routine care and to develop an evidentiary basis for interven-
tions driven by such estimates.
Thresholds for Initiating Statin Therapy
Whether a result of improved accuracy or of an overestimation
of absolute risk, the Pooled Cohort equations partially explain
the increase in statin-eligible adults with the 2013 ACC/AHA
guideline. However, the decision to lower the threshold at
which primary prevention statin treatment should be consid-
ered to an estimated 10-year absolute risk of ASCVD 7.5%
is another crucial factor. In fact, this is the lowest threshold
used by the international guidelines reviewed here. High-
risk status was defined as an estimated 10-year risk of CHD
>20% by the ATP III guidelines, fatal CVD 5% (equivalent
to 15% for nonfatal events) by the 2011 ESC/EAS guide-
lines, CVD 10% by the 2014 NICE guidelines, and 20%
by the 2012 CCS guidelines. It should be noted that because
the outcomes included in the QRISK2 risk assessment tool
endorsed by the NICE guidelines include softer diagnoses
such as angina and transient ischemic attack, the 10% esti-
mated risk by this calculation is likely to be qualitatively
similar to the 7.5% absolute risk threshold of hard stroke and
myocardial infarction events used by the 2013 ACC/AHA
guideline. Furthermore, the decision to lower the threshold to
7.5% is supported by recent evidence demonstrating both the
benefits of statin therapy in primary prevention trials includ-
ing those with relatively low risk and very small adverse event
rates in meta-analyses of statin trials including 170000 par-
ticipants.49 In a meta-analyses by the Cholesterol Treatment
Trialists Collaboration, statin treatment in people with a low
risk (<10%) of CVD resulted in an absolute reduction in major
CVD events of 11 per 1000 over 5 years for each 39-mg/dL
reduction in LDL-C, which greatly exceeded any observed
hazard of statin therapy.50 A Cochrane review of statin efficacy
in primary prevention similarly found that the number needed
to treat to prevent an adverse CVD event was 167 for those
with an estimated 5-year risk of <5% and 67 for those with
a 5-year risk of 5% to 10%.51 Moreover, using microsimula-
tion modeling, Pandya and colleagues52 recently demonstrated
that the 7.5% threshold is cost-effective, with an incremental
cost-effectiveness ratio of $37000 per quality-adjusted life-
year gained.
In addition to increasing the number of statin-eligible
adults in the United States, another important consequence of
the lowering of the treatment threshold is a reduction in the
proportion of individuals considered to be at intermediate risk,
which would decrease from 32% to 12% with full imple-
mentation of the ACC/AHA guideline.53 The most appropriate
treatment for individuals at intermediate risk is, by definition,
less certain; therefore, clinical judgment and additional testing
 Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1803
have historically been promoted for defining the treatment rec-
ommendations in this group. Significant attention has focused
on developing and validating blood and imaging biomarkers
to improve the precision of risk estimates for these individu-
als. By lowering the treatment threshold, the 2013 ACC/AHA
guideline is proposing that the recent evidence, reviewed
above, supports the use of statin therapy in most adults who
were previously in the intermediate-risk category and there-
fore that the group of individuals in whom there is equipoise
concerning the most appropriate treatment has diminished.
The international guidelines that we have reviewed endorse
basing treatment decisions on estimated absolute CVD risk.
However, recent publications have suggested potential modifi-
cations to these methods. Navar-Boggan and colleagues54 have
recently demonstrated the potential benefit of using age- and
sex-specific 10-year risk thresholds to guide therapy, includ-
ing raising the treatment threshold for adults 66 to 75 years of
age to 10% in women and 15% in men. Alternatively, Ridker
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and colleagues55 have proposed a hybrid algorithm that would
incorporate clinical trial data into the primary prevention algo-
rithm, although the superiority of this strategy is uncertain.56
These strategies warrant additional investigation to determine
whether they might be used to improve future cholesterol
guidelines.
Treatment Targets for
Lipid-Lowering Treatment
Another important modification introduced by the 2013
ACC/AHA guideline was the removal of specific treatment
targets for lipid-lowering therapy. In explaining its rationale,
the guideline committee referred to the absence of clinical
trial data indicating what the precise targets should be, the
lack of proven benefit for 1 target versus another, the inability
to account for adverse effects of striving to achieve a given
goal, and concern that target-based strategies may result
in undertreatment with statins or overtreatment with non-
statins to reach these goals.11 Additionally, there are small
but significant differences between estimating LDL-C con-
centrations with the Friedewald formula and direct measure-
ments.57 Thus, with a treat-to-target strategy, the same patient
might have different recommendations depending on the
LDL-C assay used. On the other hand, critics of this tar-
get-agnostic approach have argued that treatment goals are
valuable in clinical practice in that they serve to reinforce
patients positive behaviors and lifestyle changes and provide
patients and their providers with tangible goals and metrics.58
Furthermore, removing treatment targets makes it difficult for
patients to improve their risk profiles (by nonpharmacologi-
cal means) sufficiently to no longer warrant pharmacother-
apy. Starting a preventive medication without the possibility
of discontinuing the medication in the future may be a philo-
sophical challenge from a public health perspective because it
essentially medicalizes a large proportion of the community
while de-emphasizing the potential importance of lifestyle
modifications.
Although the most recent NICE guidelines similarly do
away with treatment targets, the latest ESC/EAS and CCS
guidelines continue to endorse treat-to-target strategies.16,18
In the ESC/EAS and CCS guidelines, the justification for
the continued use of cholesterol targets includes a number of
primary and secondary prevention statin trials demonstrat-
ing improved outcomes with more intensive LDL-C lower-
ing.49,50,5962 However, none of these trials used specific LDL-C
targets to trigger medication dose adjustments, so LDL-C
targets are extrapolated from these trials. This is a highly
controversial area in which randomized, controlled trial data
and everyday clinical practice appear to conflict. Innovative
investigative techniques are needed to evaluate the effects
of treat-to-target strategies on patient outcomes, incorporat-
ing the short-term effects of lipid lowering and the long-term
effects related to patient well-being and encouraging healthy
lifestyle behaviors.
Two developments since the publication of the 2013 ACC/
AHA guideline may further complicate the target-agnostic
approach. First is the publication of the results from the Improved
Reduction of Outcomes: Vytorin Efficacy International Trial
(IMPROVE-IT), which demonstrated a 2% absolute risk reduc-
tion of CVD events with ezetimibe added to statin therapy in
patients after myocardial infarction.10 Individuals receiving
the combination of simvastatin and ezetimibe had lower aver-
age LDL-C levels (53.2 versus 69.9 mg/dL), suggesting that
lower is better for LDL-C cholesterol, at least in the context
of secondary prevention. The second development is the recent
approval by the US Food and Drug Administration of 2 drugs
from the new class of proprotein-convertase subtilisin/kexin
type 9 inhibitors. While studies assessing the impact on hard
CVD outcomes are ongoing, these drugs appear to be safe and
effective in lowering LDL.63 The IMPROVE-IT trial was the
first to demonstrate the benefit of adding a nonstatin medication
in patients already treated with statins for secondary preven-
tion. As the options for nonstatin LDL-Clowering medications
proliferate, future guideline committees will be tasked with
evaluating whether a return to LDL-C treatment targets (at least
in certain circumstances) might be warranted to guide the addi-
tion of these new pharmacological options in certain high-risk
patients already treated with statins.64
Primary Prevention Approaches for
Those With Diabetes Mellitus or CKD
Despite variations in the language used and details about the
suggested statin dose, the international guidelines generally
agree on the approach to primary prevention in those with dia-
betes mellitus (Table2 provides details). The notable differ-
ences pertain mostly to the treatment of patients <40 years of
age, in whom there is scant evidence on the appropriateness of
statin treatment for the primary prevention of CVD.
Agreement among the guidelines is less uniform for the
treatment of individuals with CKD. The 2013 ACC/AHA
guideline is alone among the international guidelines reviewed
in not considering the presence of CKD to confer high risk.
The 2011 ESC/EAS and 2012 CCS guidelines characterize
patients with CKD as high to very high risk and recommend
statin treatment to achieve the appropriate LDL-C targets.16,18
The 2014 NICE guidelines recommend starting atorvastatin
20 mg for all patients with CKD.17 The 2013 ACC/AHA, 2011
ESC/EAS, 2014 NICE, and 2012 CSS documents all agree
that there is insufficient evidence to support specific recom-
mendations for patients with end-stage renal disease receiving
 1804CirculationMay 3, 2016
regular hemodialysis. Although the 2013 ACC/AHA guide-
line is unique among the international guidelines reviewed
in not treating all individuals with CKD as high risk, using
data from the REGARDS study, Colantonio and colleagues65
demonstrated that only 8% of individuals with CKD who are
50 to 79 years of age would not qualify for consideration of
statin therapy on the basis of the 2013 ACC/AHA guideline.
Therefore, whether this distinction between the 2013 ACC/
AHA and other guidelines actually affects individual-level
recommendations is uncertain.
Other Recent US Guidelines
Since the publication of the 2013 ACC/AHA guideline, the
US Preventive Services Task Force (USPSTF)48 and National
Lipid Association (NLA)66 have released recommendations
for CVD prevention. Agreement between the recommenda-
tions from the USPSTF draft statement (which focuses on
primary prevention) and the 2013 ACC/AHA guideline is
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generally strong. The USPSTF recommendations support the
use of the Pooled Cohort equations for absolute risk assess-
ment and suggest matching the intensity of statin therapy to
absolute risk (as opposed to the treat-to-target approach of
other guidelines). One notable difference, however, is that
the USPSTF recommendations require individuals to have a
10-year risk of ASCVD of 10% (as opposed to 7.5%) and
at least 1 cardiovascular risk factor to qualify for statin initia-
tion. For those with an estimated 10-year ASCVD risk of 7.5%
to 10%, the USPSTF states that low- to moderate-dose statins
may be considered for individuals with additional risk factors
or after a discussion with the patient about the relatively small
absolute risk reduction expected in this group.48 This distinc-
tion between the USPSTF statement and the 2013 ACC/AHA
guideline highlights several important issues previously raised
in this review, including the uncertainty of current risk predic-
tion methods and difficulties balancing the considerable costs
and potential adverse effects associated with statin use with
the small absolute risk reduction in individuals with an esti-
mated absolute 10-year ASCVD risk of <10%.
In contrast, the NLA guidelines differ substantially from
the 2013 ACC/AHA guideline.66 The NLA emphasizes count-
ing risk factors as opposed to absolute risk assessment as the
primary means of assigning risk categories, with absolute risk
to be calculated only in those with 2 major risk factors. The
NLA guidelines consider high risk to be an estimated 10-year
ASCVD risk of 15% (using the Pooled Cohort equations).
Furthermore, the NLA guidelines also endorse a treat-to-tar-
get strategy and support the use of treatment targets based on
nonHDL-C as opposed to LDL-C. With these features, the
NLA guidelines are more similar to the ATP III, 2011 ESC/
EAS, and 2012 CCS guidelines than the 2013 ACC/AHA
guideline.
Summary
The 2013 ACC/AHA guideline for cholesterol treatment made
several notable changes to the older ATP III guidelines. Of
these, the 3 most impactful are introducing the Pooled Cohort
equations as the preferred risk assessment tool, lowering the
risk threshold for considering statin in primary prevention
settings (beginning with a clinician-patient discussion) to a
10-year absolute ASCVD risk of 7.5%, and removing choles-
terol treatment targets. After reviewing several leading inter-
national guidelines, we observe a lack of consensus on the
optimal approach to risk assessment, treatment thresholds,
or the use of cholesterol targets among these guidelines. As a
result, the recommendations for primary prevention lipid-low-
ering therapy for an individual vary according to which guide-
line is followed, as illustrated by the clinical vignette. These
observations underscore the importance of further investiga-
tion aimed at refining risk prediction models and determining
the optimal strategies for monitoring and adjusting medical
therapy.
Sources of Funding
Dr Nayor was supported by training grant T32-HL007604 from the
National Institutes of Health and by the Clinical Skills Development
Core Training National Heart, Lung, and Blood Institute
U10HL110337. Dr. Vasan was supported by the National Heart,
Lung, and Blood Institutes Framingham Heart Study contracts
N01-HC-25195 and HHSN268201500001I.
Disclosures
None.
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 Recent Update to the US Cholesterol Treatment Guidelines: A Comparison With
International Guidelines
Matthew Nayor and Ramachandran S. Vasan

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 Revisiones contemporneas
Nayor y Vasan en medicina
Una comparacin cardiovascular
de las guas para el tratamiento del colesterol 41

Actualizacin reciente de las guas para el tratamiento del

colesterol en EE.UU.
Una comparacin con guas internacionales
Matthew Nayor, MD; Ramachandran S. Vasan, MD
Antecedentes Las guas para el colesterol 2013 de American College of Cardiology/American Heart Association (ACC/
AHA) recomendaron varios cambios de las guas previas Adult Treatment Panel III. Asumiendo su plena implementacin,
las guas ACC/AHA 2013 identificaran 13 millones de americanos como recientemente elegibles para la consideracin del
tratamiento con estatinas. Tres caractersticas de las guas ACC/AHA 2013 primariamente responsables de estas diferencias
son la herramienta de evaluacin del riesgo especfico aprobada, el umbral de riesgo considerado suficiente para justificar el
tratamiento con estatinas en prevencin primaria, y la decisin de no incluir objetivos del tratamiento del colesterol. No hay
consenso entre las guas internacionales sobre el abordaje ptimo de estos 3 componentes. Las guas ACC/AHA 2013 reco-
miendan la evaluacin del riesgo absoluto con las ecuaciones de la Cohorte Agrupada que se desarrollaron para mejorar sobre
los modelos previos de evaluacin del riesgo mediante la inclusin del accidente cerebrovascular como resultado y mediante
la ampliacin de la diversidad racial y geogrfica. Cada una de las guas internacionales destacadas recomienda una ecuacin
diferente para la evaluacin del riesgo absoluto. Las guas ACC/AHA 2013 aconsejan la consideracin del tratamiento con
estatinas para un riesgo estimado de 10 aos de enfermedad vascular ateroesclertica de 7,5%, que es ms bajo que los
umbrales recomendados por otras guas internacionales destacadas. Por ltimo, las guas ACC/AHA 2013 no aprueban una
estrategia de tratar segn un objetivo (treat-to-target) pero en su lugar especifican la intensidad apropiada de estatinas para
cada categora de riesgo. Este abordaje es compartido por las guas del National Institute for Health and Care Excellence,
pero difiere de otras guas internacionales. En esta revisin, resumimos las recomendaciones de las guas de colesterol ACC/
AHA 2013 y las comparamos con las recomendaciones del Adult Treatment Panel III y otras guas internacionales destacadas.
(Circulation. 2016;133:1795-1806. DOI: 10.1161/CIRCULATIONAHA.116.021407.)
Palabras clave: enfermedades cardiovasculares colesterol gua [tipo de publicacin] prevencin y control

A pesar de las reducciones de la tasa de mortalidad por en-

fermedad cardiovascular (ECV) entre los pases de altos
y medianos ingresos durante las 2 dcadas pasadas, aproxima-
damente un tercio del total de las muertes son an atribuibles
a enfermedad cardaca isqumica y accidente cerebrovascular.1
Estas condiciones tambin dan cuenta de una gran proporcin
de discapacidad y costos en atencin de la salud globales.2,3 El
colesterol plasmtico elevado se encuentra entre los factores de
riesgo cardiovascular modificables ms prevalentes, con trata-
mientos mdicos probados para reducir tanto la incidencia de
ECV como la mortalidad relacionada.4-10 Por lo tanto, las guas
de prctica clnica dirigidas al tratamiento del colesterol plasm-
tico tienen un impacto potencial tremendo sobre la salud de la
poblacin y los costos de atencin de la salud relacionados. Las
guas de EE.UU. ms recientes para el tratamiento del colesterol
plasmtico11 contienen cambios importantes de la versin pre-
via.12,13 En esta revisin, nos proponemos resumir las recomen-
daciones de las guas de colesterol de EE.UU. ms recientes,
destacando los cambios especficos de la versin previa, y en
paralelo compararla con otras guas internacionales destacadas.
Guas para el tratamiento del colesterol plasmtico
Vieta clnica
Para mostrar las diferencias entre las diversas guas, nos referi-
mos a un paciente representativo (Figura): Considerar un hom-
Del Framingham Heart Study, Framingham, MA (M.N., R.S.V.); Brigham and Womens Hospital, Division of Cardiovascular Medicine, Boston, MA
(M.N.); Sections of Preventive Medicine and Cardiology, Boston University School of Medicine, MA (R.S.V.); and Department of Epidemiology, Boston
University School of Public Health, MA (R.S.V.).
Correspondencia a Matthew Nayor, MD, Cardiovascular Division, Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115. Correo electr-
nico mnayor@partners.org
2016 American Heart Association, Inc.
Circulation est disponible en http://circ.ahajournals.org
41
bre blanco no fumador de 69 aos de edad sin ECV establecida
ni diabetes mellitus, sin historia familiar de ECV prematura,
que actualmente no toma medicamentos. Tiene 69 pulg (175
cm) de estatura y pesa 180 lb (81,6 kg); su ndice de masa
corporal es de 26,6 kg/m2; su tensin arterial es de 144/86
mmHg y su perfil lipdico en ayunas revela un colesterol s-
rico total de 195 mg/dl, colesterol de la lipoprotena de baja
densidad (LDL) de 125 mg/dl, colesterol de la lipoprotena de
alta densidad (HDL) de 50 mg/dl, y triglicridos de 100 mg/dl
(para convertir de mg/dl a mmol/l, multiplicar LDL o HDL por
0,0259 y multiplicar triglicridos por 0,0113).
Guas 2013 de American College of Cardiology/
American Heart Association
Metodologa
Las guas 2013 de American College of Cardiology/American
Heart Association Guideline on the Treatment of Blood
Cholesterol to Reduce Atherosclerotic Cardiovascular Risk
in Adults11 (gua ACC/AHA 2013) fue encargada de reflejar
una nueva evidencia ya que las previas guas Adult Treatment
Panel III (ATP III) fueron actualizadas por ltima vez en
2004.12,13 Mientras que las guas de colesterol previas se en-
focaron en la prevencin de la enfermedad cardaca coronaria
(EC), las guas ACC/AHA 2013 ampli el foco a ECV ate-
roesclertica (ECV AS), incluyendo EC, accidente cerebro-
DOI: 10.1161/CIRCULATIONAHA.116.021407
42 Circulation Octubre 2016

Hombre blanco de 60 aos de edad

Estatura: 69 pulg
(175 cm)
Recomendaciones de acuerdo con diferentes guas
Historia clnica
Sin medicaciones Gua Evaluacin de riesgo Recomendacin
No fumador global a 10 aos de estatinas
Sin ECV (resultado)
Sin historia familiar de ECV
ACC/AHA 2013 10,3% (ECV AS) S

TA: 144/86
mmHg Lpidos plasmticos ATP III 10% (EC) No
Colesterol total: 195 mg/dl
LDL: 125 mg/dl
HDL: 50 mg/dl ESC/EAS 2011 3-5% (mortalidad ECV) S
Triglicridos: 100 mg/dl

NICE 2014 10,4% (ECV) S

CCS 2012 16,6% (ECV) No

Peso: 180 libras (81,6 kg)

ndice de masa corporal 26,6 kg/m2

Figura. Vieta clnica y recomendaciones de acuerdo con diferentes guas internacionales. ACC indica American College of Cardiology;
AHA, American Heart Association; ECV AS, enfermedad cardiovascular ateroesclertica; ATP III, Adult Treatment Panel III; CCS, Canadian
Cardiovascular Society; EC, enfermedad cardaca coronaria; ECV, enfermedad cardiovascular; EAS, European Atherosclerosis Society;
ESD, European Society of Cardiology; HDL, colesterol de la lipoprotena de alta densidad; LDL, colesterol de la lipoprotena de baja den-
sidad; y NICE, National Institute for Health and Care Excellence.

vascular y enfermedad arterial perifrica. El equipo de tareas
ACC/AHA 2013 utiliz un nuevo abordaje para evaluar la
evidencia disponible, poniendo el foco en los estudios contro-
lados aleatorizados y revisiones sistemticas y metaanlisis de
estudios controlados aleatorizados. Adems, las nuevas guas
difirieron de las previas en su mbito de aplicacin. Mientras
que las guas ATP III incluan una revisin tpica amplia y
recomendaciones para evaluacin de laboratorio, diagnstico
clnico, intervenciones en el estilo de vida y tratamiento far-
macolgico, las guas ACC/AHA 2013 se enfocaron en res-
ponder 3 cuestiones crticas: (1) Cul es la evidencia de los
objetivos de LDL y no-HDL en la prevencin secundaria de
ECV AS? (2) Cul es la evidencia de los objetivos de LDL
y no-HDL en la prevencin primaria de ECV AS? (3) Cul
es la eficacia y seguridad de los frmacos modificadores de
lpidos en la prevencin primaria y secundaria de ECV AS?11
Un profesional independiente contratado seleccion los estu-
dios relevantes para ser revisados para cada cuestin crtica de
acuerdo con los criterios preespecificados. Esta metodologa
fue diseada para reducir el sesgo y asegurar que los estudios
de baja calidad no fueran considerados cuando se formulasen
las recomendaciones.
Modelo de evaluacin del riesgo
Con las guas ACC/AHA 2013 se introdujo una nueva herra-
mienta para la evaluacin del riesgo global.11 Las guas pre-
vias recomendaban utilizar un Framingham Risk Score (FRS)
modificado para estimar el riesgo a 10 aos de infarto de mio-
cardio o muerte por EC. Las crticas a este modelo incluyeron
la ausencia de accidente cerebrovascular como resultado de
una falta de diversidad racial, tnica y geogrfica en la pobla-
cin de derivacin. En respuesta, las ecuaciones de la Cohorte
Agrupada se obtuvieron con datos de National Heart, Lung
and Blood Institute -4 estudios de cohorte patrocinados- el
estudio Atherosclerosis Risk in Communities (ARIC), el estu-
dio Cardiovascular Health Study (CHS), el estudio Coronary
Artery Risk Development in Young Adults (CARDIA), y el
Framingham Heart Study (FHS; incluyendo cohortes origina-
les y de la descendencia) - con resultados clnicos adjudicados,
incluyendo infarto de miocardio, muerte por EC y accidente
cerebrovascular fatal y no fatal.14 Los factores de riesgo que re-
nen los criterios de inclusin en el modelo multivariable fue-
ron edad, sexo, colesterol total, HDL, tensin arterial sistlica,
estado del tratamiento antihipertensivo, diabetes mellitus y es-
tado del hbito de fumar actual. De estas variables, slo la dia-
betes mellitus no fue incluida en el FRS modificado aprobado
por las guas ATP III. Se construyeron diferentes modelos mul-
tivariables para individuos blancos y negros, y se recomend
precaucin cuando estas ecuaciones se aplicaron a otras razas y
adultos fuera de los rangos de edad de 40 a 79 aos.
Recomendaciones de tratamiento
Las guas ACC/AHA 2013 recomendaron el tratamiento con
inhibidores de la 3-hidroxi-3-metilglutaril-coenzima A reduc-
tasa (estatinas) para 4 categoras de individuos: (1) preven-
cin secundaria para aquellos con ECV AS establecida, (2)
prevencin primaria de ECV AS para aquellos con LDL 190
mg/dl, (3) prevencin primaria de ECV AS para individuos con
diabetes mellitus y LDL de 70 a 189 mg/dl, y (4) prevencin
primaria de ECV AS para aquellos sin diabetes mellitus, con
LDL de 70 a 189 mg/dl, pero con un riesgo absoluto a 10 aos
estimado de 7,5% evaluado por las ecuaciones de la Cohorte
Agrupada. Para este cuarto grupo en especial, los autores de las
guas enfatizan la importancia de tomar las decisiones de for-
ma compartida con base en una discusin detallada del riesgo
entre el paciente y el mdico antes de la iniciacin del trata-
 Nayor y Vasan Una comparacin de las guas para el tratamiento del colesterol
miento con estatinas.15 La discusin mdico-paciente debera
incluir una evaluacin del beneficio potencial, posibles efectos
adversos e interacciones medicamentosas, cambios en el estilo
de vida, manejo de otros factores de riesgo y por supuesto las
preferencias del paciente. De manera adicional, otros factores
que pueden afectar la reclasificacin del riesgo neto podran
utilizarse para informar mejor la decisin de tratamiento; stos
incluyen LDL 160 mg/dl o evidencia de dislipidemia genti-
ca, riesgo de vida elevado, historia familiar de ECV prematura,
niveles plasmticos de protena C-reactiva de alta sensibilidad
2,0 mg/l, ndice tobillo braquial <0,9, o puntaje de calcio de
la arteria coronaria anormal (300 unidades Agatston o 75
percentilo por edad, sexo y etnicidad). Los individuos con ries-
go intermedio (5%-7,4% de riesgo absoluto a 10 aos) o bajo
riesgo (<5% de riesgo absoluto a 10 aos) podran tambin
considerarse para el tratamiento con estatinas sobre la base de
las preferencias del paciente o del beneficio percibido basado
en factores adicionales como aquellos listados ms arriba.
En lugar de establecer objetivos especficos de LDL, las
guas ACC/AHA 2013 en esencia sugirieron una dosis fija (o
intensidad) de estatinas para cada categora de riesgo, con la
intencin de una reduccin del LDL del 30% al 49% y 50%
para estatinas de moderada y alta intensidad respectivamente.
Los autores tambin sugirieron que las medicaciones no esta-
tinas podan considerarse para aquellos en alto riesgo (preven-
cin secundaria, diabetes mellitus, LDL 190 mg/dl) si tienen
intolerancia a la dosis recomendada de estatinas o tienen una
respuesta inadecuada a las estatinas. Aunque no se aprobaron
objetivos de LDL especficos, las guas ACC/AHA 2013 reco-
mendaron el monitoreo de los niveles de lpidos plasmticos
para asegurar adherencia, respuesta teraputica y seguridad.
En comparacin, las guas ATP III recomendaron una estra-
tegia para tratar segn el objetivo con la finalidad de LDL es-
pecficos para cada grupo de riesgo. Para la prevencin prima-
ria, la meta de LDL se puso a <100 mg/ml para los individuos
de alto riesgo (riesgo de EC a 10 aos >20%), <130 mg/dl para
aquellos en riesgo intermedio (riesgo de EC a 10 aos, 10%-
20%), y <160 mg/dl para los individuos de bajo riesgo (riesgo
de EC a 10 aos <10%). La meta de LDL para prevencin
secundaria o prevencin primaria de ECV en aquellos con dia-
betes mellitus fue <100 mg/dl, con la opcin de apuntar a <70
mg/dl para aquellos con el riesgo ms alto de ECV.12,13
En resumen, las diferencias ms importantes entre las guas
ACC/AHA 2013 y las guas ATP III son la introduccin de
las ecuaciones de la Cohorte Agrupada, la eliminacin de los
objetivos de tratamiento de LDL y la disminucin del umbral
al cual las estatinas deberan considerarse para un riesgo ab-
soluto a 10 aos estimado de 7,5%. Las diferencias entre estos
2 documentos se resumen en la Tabla 1. Para proveer un con-
texto adicional para las guas ACC/AHA 2013, a continuacin
compararemos sus recomendaciones con aqullas de otras
guas internacionales destacadas, como se seala en la Tabla 2.
Vieta clnica
Con las ecuaciones de la Cohorte Agrupada, el paciente de
nuestra vieta clnica tendra un riesgo estimado de ECV AS
absoluto a 10 aos del 10,3%, y podra considerarse un trata-
miento con estatinas de moderada a alta densidad despus de
una discusin mdico-paciente de la potencial reduccin del
riesgo, efectos adversos, interacciones medicamentosas y pre-
ferencias del paciente. Con el FRS modificado aprobado por
las guas ATP III, por otra parte, l sera considerado en riesgo
intermedio sobre la base de un riesgo absoluto a 10 aos es-
43
timado de EC del 10%. Por consiguiente, su objetivo de LDL
sera <130 mg/dl, y dado su actual LDL de 125 mg/dl, l no
recibira tratamiento con estatinas.
Notablemente, fue utilizado un hombre blanco para nuestra
vieta clnica representativa. La diferencia en el riesgo esti-
mado entre las ecuaciones de la Cohorte Agrupada y el FRS
sera ms pronunciada si una mujer negra, por ejemplo, tuvie-
se el mismo perfil de factor de riesgo. Con las ecuaciones de
la Cohorte Agrupada, ella tendra un riesgo de ECV AS a 10
aos de 7,4%, que es considerablemente ms alto que el 2% de
riesgo de EC a 10 aos estimado por el FRS.
Guas 2011 de European Society of Cardiology/
European Atherosclerosis Society
Metodologa
Las Guidelines for the Management of Dyslipidaemias16 de
la European Society of Cardiology/European Atherosclerosis
Society (guas 2011 ESC/EAS) son un documento amplio di-
rigido a la evaluacin del riesgo cardiovascular, evaluacin de
laboratorio, modificaciones de estilo de vida, tratamiento far-
macolgico y el abordaje de cuadros clnicos especficos como
las dislipidemias familiares. La fuerza de tareas de ESC/EAS
bas sus hallazgos en una amplia revisin de la literatura en
la que la mayor confianza fue colocada en los resultados de
estudios controlados aleatorizados, pero que fue inclusiva de
todos los diseos de estudio.
Modelo de evaluacin de riesgo
De manera similar a las guas ACC/AHA 2013, las guas 2011
ESC/EAS apoyan el uso de rutina de la evaluacin del riesgo
cardiovascular global para todos los adultos sin ECV estable-
cida pero aprobaron el uso de la herramienta de evaluacin
de riesgo Systemic Coronary Risk Evaluation (SCORE). La
herramienta SCORE, derivada de los datos agregados de estu-
dios de cohorte con participantes de 12 pases europeos, est
diseada para estimar el riesgo a 10 aos de un evento ECV fa-
tal.19 La decisin de incluir solamente eventos de resultado fa-
tal se bas en la evaluacin de que los eventos fatales son ms
fcilmente calibrados en diferentes poblaciones y son menos
probables que los eventos no fatales de ser afectados por varia-
ciones geogrficas locales en el diagnstico y tratamiento.19 La
tasa de eventos de ECV total (incluidos eventos no fatales) ha
mostrado ser 3 veces ms alta que la tasa de eventos ECV fa-
tales.16 Las variables incluidas en el modelo de riesgo SCORE
incluyen edad, sexo, tensin arterial sistlica, colesterol total
y estado del hbito de fumar, y se utilizan modelos separados
para pases europeos de alto y bajo riesgo.
Recomendaciones de tratamiento
De acuerdo con las guas 2011 ESC/EAS, los pacientes se con-
sideran de muy alto riesgo por ECV documentada, diabetes
mellitus tipo 2, diabetes mellitus tipo 1 con dao de rgano
blanco, enfermedad renal crnica moderada a severa (ERC),
o riesgo absoluto a 10 aos estimado de ECV fatal 10%. Los
individuos de alto riesgo son aquellos con un riesgo a 10 aos
de ECV fatal del 5% al 9,9% o elevaciones marcadas de facto-
res de riesgo como dislipidemia familiar o hipertensin severa.
El riesgo moderado se define como riesgo a 10 aos de ECV
fatal de 1% a 4,9%, y bajo riesgo se define como un riesgo a
10 aos de evento ECV fatal estimado <1%. Extrapolando de
estudios clnicos, la fuerza de tareas recomend metas de LDL
de aproximadamente <70 mg/dl (1,8 mmol/l) para muy alto
44 Circulation Octubre 2016

Tabla 1. Comparacin de las guas ACC/AHA 2013 y ATP III para el tratamiento del colesterol plasmtico
Criterios Guas ACC/AHA 201311 Guas ATP III 200112 con actualizacin 200413
Foco de prevencin primaria ECV AS, incluyendo accidente cerebrovascular, y enfermedad arterial EC
perifrica
mbito de las guas Limitado a tres cuestiones crticas: evidencia de objetivos de Documento abarcativo, incluyendo revisin de
colesterol en prevencin secundaria, evidencia de objetivos de literatura, diagnstico y evaluacin, tratamiento,
colesterol en prevencin primaria, y efectividad y seguridad de las cambio de estilo de vida y marcos clnicos
drogas modificadoras de lpidos especiales
Evidencia considerada Estudios controlados, aleatorizados y metaanlisis de estudios Revisin sistemtica inclusiva
controlados, aleatorizados
Herramienta de evaluacin del Ecuaciones de riesgo de la Cohorte Agrupada: FRS modificado:
riesgo Objetivos primarios: muerte por EC, IM no fatal, accidente Objetivos primarios: muerte por EC, IM no fatal
cerebrovascular fatal o no fatal Muestra de derivacin: principalmente poblacin
Muestra de derivacin: datos agrupados de 4 estudios de cohorte blanca de ascendencia europea
Factores pronsticos seleccionados en el modelo multivariable: Factores pronstico seleccionados en el modelo
edad, sexo, colesterol total, HDL, tensin arterial sistlica, estado del multivariable: edad, sexo, colesterol total, HDL,
tratamiento antihipertensivo, diabetes mellitus, y estado del hbito de tensin arterial sistlica, estado del tratamiento
fumar actual antihipertensivo, y estado del hbito de fumar actual
Consideraciones adicionales: modelos separados creados para
hombres y mujeres y para blancos y negros
Objetivos de tratamiento del No S
colesterol aprobados
Tratamiento de disminucin de LDL 190 mg/dl: estatina con alta intensidad LDL 190 mg/dl
lpidos para prevencin primaria en LDL 70-189 mg/dl y: 2 factores de riesgo clnico y:
aquellos sin diabetes mellitus Riesgo a 10 aos 7,5%: estatina con alta intensidad despus de Alto riesgo (riesgo a 10 aos >20%) y LDL 100
discusin mdico-paciente mg/dl (70 mg/dl opcional): estatina
Riesgo a 10 aos <7,5%: se puede considerar estatina con Riesgo intermedio (riesgo a 10 aos, 10%-20%) y
moderada intensidad despus de considerar otros factores* y con LDL 130 mg/dl (100 mg/dl opcional): estatina
base en una discusin mdico-paciente Bajo riesgo (riesgo a 10 aos <10%) y LDL 160
mg/dl: se puede considerar estatina
Tratamiento de disminucin de LDL 70 mg/dl y: LDL 100 mg/dl: estatina
lpidos para prevencin primaria en Riesgo a 10 aos 7,5%: estatina con alta intensidad LDL 70 mg/dl con caractersticas de alto riesgo
aquellos con diabetes mellitus Riesgo a 10 aos <7,5%: estatina con moderada intensidad (opcional): estatina
Tratamiento de disminucin de Estatina con alta intensidad S LDL 100 mg/dl (70 mg/dl opcional): estatina
lpidos para prevencin secundaria
Objetivos de no-LDL No discutido Objetivos de HDL y triglicridos discutidos en detalle
Recomendaciones especficas para Ecuaciones de riesgo de cohorte agrupada no validadas para edad FRS modificado no validado para edad 65 aos
la vejez >79 aos Juicio clnico recomendado en adultos mayores
Considerar estatina con baja intensidad si edad >75 aos
ACC/AHA indica American College of Cardiology/American Heart Association; ECV AS, enfermedad cardiovascular ateroesclertica; ATP III, Adult Treatment Panel III;
EC, enfermedad cardaca coronaria; FRS, Framingham Risk Score; HDL, colesterol de la lipoprotena de alta densidad; LDL colesterol de la lipoprotena de baja densidad;
e IM, infarto de miocardio.
*Otros factores a considerar incluyen LDL 160 mg/dl, historia familiar, protena C reactiva de alta sensibilidad, puntaje de calcio arterial coronario, ndice tobillo-
braquial, y riesgo de vida.
Factores de riesgo clnico incluye hombre de edad 45 aos, mujer de edad 55 aos, historia familiar de EC prematura, hbito de fumar actual, hipertensin
(140/90 mmHg o con medicacin antihipertensiva), y lipoprotena de alta densidad <40 mg/dl.

riesgo, <100 mg/dl (2,5 mmol/l) para alto riesgo, <115mg/dl
(3,0 mmol/l) para riesgo moderado, y <190 mg/dl (4,9 mmol/l)
para bajo riesgo. Por lo tanto, las guas 2011 ESC/EAS difie-
ren de las guas ACC/AHA 2013 en la eleccin del modelo de
evaluacin de riesgo, el riesgo estimado a 10 aos se consider
suficiente para justificar tratamiento mdico, y la aprobacin
continuada de objetivos de LDL para guiar el tratamiento.
Vieta clnica
De acuerdo con la herramienta de evaluacin del riesgo
SCORE, nuestro paciente tiene un riesgo estimado a 10 aos
de mortalidad por ECV de 5% si vive en un pas europeo de
alto riesgo y sera considerado de alto riesgo. Si l vive en
un pas de bajo riesgo, sin embargo, su riesgo estimado a 10
aos de muerte por ECV sera del 3%, y por lo tanto sera con-
siderado de riesgo moderado. Independientemente de su pas
de residencia, el tratamiento con estatinas sera recomendado,
dado los objetivos de LDL de <100 mg/dl para alto riesgo y
<115 mg/dl para individuos de riesgo moderado.
Guas 2014 de National Institute for Health and
Care Excellence
Metodologa
Las guas para la modificacin de lpidos del National Institute
for Health and Care Excellence (NICE) en Inglaterra fueron
actualizadas por ltima vez en 2014.17 Las guas NICE son de
alcance similar a las guas ACC/AHA 2013, con recomenda-
ciones para la prevencin primaria y secundaria de ECV. De
las guas internacionales revisadas, las guas NICE son nota-
bles por la especificidad de las recomendaciones farmacolgi-
cas provistas y por el grado en el que se utilizan los anlisis
costo-eficacia para justificar las recomendaciones.
Modelo de evaluacin de riesgo
Las guas NICE apoyan el uso de la herramienta de evaluacin
de riesgo QRISK2 para la evaluacin del riesgo cardiovascular
global en todos los adultos <84 aos de edad libres de ECV.
El modelo QRISK2 estima el riesgo absoluto a 10 aos de
 Nayor y Vasan Una comparacin de las guas para el tratamiento del colesterol 45

Tabla 2. Comparacin de guas internacionales para el tratamiento del colesterol plasmtico

Criterios Guas ACC/AHA 201311 Guas ESC/EAS 201116 Guas NICE 201417 Guas CCS 201218
Evidencia Estudios controlados, Revisin de literatura Revisin de literatura abarcativa Revisin de literatura
considerada aleatorizados abarcativa abarcativa
Herramienta de Ecuaciones de la Cohorte Herramienta de evaluacin Herramienta de evaluacin de riesgo FRS para ECV total
evaluacin del riesgo Agrupada de riesgo SCORE QRISK2
Objetivos Muerte por EC, IM no fatal, Muerte por EC o accidente Muerte por EC, EC (IM o angor), Muerte por EC, IM,
primarios accidente cerebrovascular fatal cerebrovascular fatal (el accidente cerebrovascular, o insuficiencia coronaria, angor,
o no fatal total de eventos ECV es 3 accidente isqumico transitorio accidente cerebrovascular
veces ms alto que la tasa de isqumico o hemorrgico,
evento fatal) accidente isqumico
transitorio, enfermedad
arterial perifrica, insuficiencia
cardaca
Muestra de la Datos agrupados de 4 cohortes Datos agrupados de 12 Poblacin britnica, actualizado Principalmente poblacin
derivacin pases europeos anualmente blanca de ascendencia
europea
Factores Edad, sexo, colesterol total, Edad, sexo, colesterol total, Edad, sexo, colesterol total, HDL, Edad, sexo, colesterol total,
pronstico HDL, tensin arterial sistlica, tensin arterial sistlica, y tensin arterial sistlica, estado del HDL, tensin arterial sistlica,
seleccionados estado del tratamiento estado del hbito de fumar tratamiento antihipertensivo, diabetes estado del tratamiento
en el modelo antihipertensivo, diabetes (modelos separados para mellitus, estado del hbito de fumar, antihipertensivo, diabetes
multivariable mellitus y estado del hbito pases de alto y bajo riesgo) etnicidad, historia familiar de EC, mellitus y estado del hbito
de fumar (modelos separados ndice de masa corporal, deprivacin de fumar
creados para blancos y negros) socioeconmica, artritis reumatoidea,
ERC, y fibrilacin auricular
Objetivos de No S (LDL) No S (LDL)
tratamiento de Considerar ApoB o no-HDL Considerar ApoB o no-HDL
colesterol aprobados como objetivo alternativo como objetivo alternativo
Tratamiento de LDL 190 mg/dl LDL 190 mg/dl Riesgo a 10 aos 10% o ERC LDL 190 mg/dl
disminucin LDL 70-189 mg/dl y: LDL <190 mg/dl y: LDL <190 mg/dl y riesgo a 10
de lpidos para Riesgo a 10 aos 7,5% Riesgo a 10 aos 10% aos 5%-9% (opcional)
prevencin primaria despus de discusin ERC moderada a severa LDL 130 mg/dl y riesgo a 10
en aquellos sin mdico-paciente LDL 100 mg/dl y: aos 10%-19%
diabetes mellitus Riesgo a 10 aos <7,5% Riesgo a 10 aos 5%-9,9% LDL 75 mg/dl y:
despus de consideracin de Factores de riesgo severo Riesgo a 10 aos 20%
otros factores y con base en LDL 115 mg/dl y riesgo a ERC o proteinuria
discusin mdico-paciente 10 aos 1%-4,9% Hipertensin de alto riesgo*
Tratamiento de LDL 70 mg/dl Diabetes mellitus tipo 2 y Diabetes mellitus tipo 2 y riesgo a 10 Edad 40 aos o <40 aos
disminucin LDL 100 mg/dl aos 10% y duracin de la enfermedad
de lpidos para Diabetes mellitus tipo 2 de Diabetes mellitus tipo 1 y edad >40 >15 aos, o edad >30
prevencin primaria alto riesgo y LDL 70 mg/dl aos, duracin de la enfermedad aos con complicaciones
en aquellos con Diabetes mellitus tipo 1 y >10 aos, nefropata, o factores de microvasculares
diabetes mellitus dao de rgano blanco riesgo ECV
ERC considerada No S S S
una caracterstica de
alto riesgo
Recomendaciones Ecuaciones de riesgo de la SCORE validado para edades QRISK2 est calibrado a edad 84 FRS para usarse en edad 75
especficas para la cohorte agrupada no validadas 40-65 aos aos aos
vejez para edad >79 aos Juicio clnico recomendado Juicio clnico recomendado en
Considerar estatina de baja en la vejez aquellos >75 aos
intensidad
Consideraciones Riesgo de vida Objetivos de no-LDL Objetivos de no-LDL Objetivo de edad
adicionales para la cardiovascular y no-LDL
evaluacin de riesgo
ACC/AHA indica American College of Cardiology/American Heart Association; ApoB, apolipoprotena B; CCS, Canadian Cardiovascular Society; EC, enfermedad car-
daca coronaria; ERC, enfermedad renal crnica; ECV, enfermedad cardiovascular; ESC/EAS European Society of Cardiology/European Atherosclerosis Society; FRS,
Framingham Risk Score; HDL, colesterol de lipoprotena de alta densidad; LDL, colesterol de lipoprotena de baja densidad; IM, infarto de miocardio; NICE, National
Institute for Health and Care Excellence; y SCORE, Systemic Coronary Risk Evaluation.
*Hipertensin de alto riesgo se define como hipertensin ms 3 de los siguientes factores de riesgo: hombre, edad >55 aos, fumador, proporcin colesterol total/
HDL >6, hipertrofia ventricular izquierda, historia familiar de ECV prematura, anormalidades ECG o microalbuminuria.
Diabetes mellitus tipo 2 de alto riesgo se define como diabetes mellitus ms 1 de los siguientes factores de riesgo: ECV establecida, ERC, edad >40 aos, y uno o
ms factores de riesgo cardiovascular o dao de rgano blanco.

EC (angor o infarto de miocardio), accidente cerebrovascu-
lar, o accidente isqumico transitorio; est especficamente
calibrado para la poblacin britnica y se actualiza anualmen-
te. Comparado con las ecuaciones de la Cohorte Agrupada y
la herramienta de evaluacin del riesgo SCORE, el modelo
multivariable QRISK2 incluye factores de riesgo adicionales
tales como etnicidad, historia familiar de EC prematura, de-
privacin socioeconmica, ndice de masa corporal, artritis
reumatoidea, ERC y fibrilacin auricular (adems de edad,
sexo, tensin arterial sistlica, colesterol total, HDL, estado
46 Circulation Octubre 2016
del tratamiento de la hipertensin, diabetes mellitus y estado
del hbito de fumar, que estn incluidos en las ecuaciones de
la Cohorte Agrupada).20
Recomendaciones de tratamiento
De manera semejante a las guas ACC/AHA 2013, las guas
NICE 2014 no aprueban una estrategia de tratar segn un ob-
jetivo. En cambio, el tratamiento con estatinas se recomienda
para la prevencin primaria en individuos con diabetes melli-
tus tipo 2 o en aquellos sin diabetes mellitus pero con un riesgo
de ECV absoluto a 10 aos estimado 10%. El tratamiento
con estatinas tambin se recomienda para pacientes con dia-
betes mellitus tipo 1 que tienen >40 aos de edad con una du-
racin de la enfermedad >10 aos o con evidencia de dao
de rgano blanco. Se recomienda atorvastatina 20 mg por da
para prevencin primaria, y atorvastatina 80 mg por da para
prevencin secundaria. En los pacientes con ERC, se sugiere
atorvastatina 20 mg para prevencin primaria y secundaria.
Vieta clnica
El paciente de nuestra vieta clnica tiene un riesgo de ECV
estimado a 10 aos de 10,4% con el modelo QRISK2, y reu-
nira as los criterios para tratamiento con estatinas como pre-
vencin primaria.
Guas 2012 de Canadian Cardiovascular Society
Metodologa y modelo de evaluacin del riesgo
Las guas de la Canadian Cardiovascular Society (CCS) para
el diagnstico y tratamiento de la dislipidemia para la preven-
cin de ECV en adultos fue actualizada por ltima vez en 2012
(guas CCS 2012).18 Las guas CCS 2012 recomiendan utilizar
el FRS para eventos de la ECV total para estimar el riesgo
absoluto a 10 aos. Estas guas tambin sugieren duplicar el
riesgo absoluto estimado para individuos con historia familiar
de ECV prematura sobre la base de la evidencia de un aumento
de 2 veces el riesgo de ECV para los participantes de FHS con
una historia familiar de ECV prematura.21 Los autores de las
guas CCS 2012 aconsejan considerar la edad cardiovascu-
lar adems del riesgo absoluto estimado a 10 aos cuando
se discute el tratamiento de disminucin de lpidos con los
pacientes. Edad cardiovascular y edad del corazn pue-
den ser conceptos ms fciles de entender por los pacientes
y pueden facilitar de este modo el compartir la decisin entre
paciente y mdico.22
Recomendaciones de tratamiento
Las guas CCS 2012 aprueban una estrategia de tratar segn
el objetivo con metas de LDL de <75 mg/dl (2,0 mmol/l) para
los pacientes de alto riesgo (riesgo absoluto a 10 aos 20%,
ERC, o hipertensin de alto riesgo), <130 mg/dl (3,5 mmol/l)
para los individuos de riesgo intermedio (riesgo absoluto a 10
aos, 10%-19%), y <190 mg/dl (5 mmol/l) para aquellos de
bajo riesgo (riesgo absoluto a 10 aos <10%). Un objetivo de
LDL de <75 mg/dl se recomienda tambin para aquellos con
diabetes mellitus y para prevencin secundaria, con una meta
de <70 mg/dl (1,8 mmol/l) considerado opcional para aquellos
con el riesgo ms alto.
Vieta clnica
El paciente de nuestra vieta clnica tiene un riesgo esti-
mado de 10 aos de ECV total de 16,6% de acuerdo con el
FRS y debera caracterizarse como de riesgo intermedio. El
objetivo de LDL para el grupo de riesgo intermedio es <130
mg/dl. Por lo tanto, no se le debera recomendar recibir tra-
tamiento con estatinas.
Comparacin de las guas internacionales
Las guas ACC/AHA 2013 difieren sustancialmente de su ver-
sin previa, las guas ATP III, y de otras guas internaciona-
les destacadas. Los efectos de estos cambios se ilustraron con
nuestra vieta clnica representativa, en la que las recomenda-
ciones para iniciar tratamiento con estatinas para un hombre de
60 aos de edad con factores de riesgo cardiometablico mo-
destos difirieron de acuerdo con las guas seguidas (Figura).
Las guas internacionales destacadas incluidas en esta revisin
difieren en 3 reas clave: el modelo de evaluacin de riesgo
sugerido (factores de riesgo componentes y resultado evalua-
do), el umbral de riesgo considerado suficiente para justificar
la iniciacin de tratamiento mdico, y la decisin de si usar
una estrategia para tratar segn el objetivo.
Impacto previsto de los cambios propuestos por
las guas ACC/AHA 2013
La dislipidemia y los factores de riesgo cardiometablico son
altamente prevalentes en la poblacin; por lo tanto los cam-
bios en las guas de tratamiento del colesterol afectarn las re-
comendaciones de tratamiento para mucha gente. Utilizando
datos de las National Health and Nutrition Examination
Surveys (NHANES), Pencina y colegas demostraron que 13
millones de adultos americanos seran elegibles para iniciar
tratamiento con estatinas con la implementacin plena de
las guas ACC/AHA 2013.23 El aumento en la elegibilidad de
las estatinas fue principalmente atribuible a una proporcin
ms alta de individuos de 60 a 75 aos de edad que renen
criterios para tratamiento, que creci de 47,8% con las guas
ATP III a 73,3% con las guas ACC/AHA 2013. El verdade-
ro impacto de las guas ACC/AHA 2013 probablemente est
sobreestimado por estos clculos, que asumen que todos los
individuos en un grupo con beneficio de las estatinas seran
tratados con estatinas y por lo tanto no consider el efecto de
una discusin mdico-paciente (especficamente enfatizado
por las nuevas guas) de los riesgos y beneficios de comen-
zar con estatinas. No obstante, se predice que las guas ACC/
AHA 2013 darn como resultado un nmero mayor de indivi-
duos elegibles para estatinas en los Estados Unidos.
El impacto general de una proporcin mayor de poblacin
que recibe tratamiento con estatinas es incierto. Aunque el so-
bretratamiento es una preocupacin,24 varios estudios recientes
han sugerido que las guas ACC/AHA 2013 se alinean ms es-
trechamente que las guas ATP III con la carga ateroesclertica
coronaria, evaluada con el puntaje de calcio arterial coronario
y la angiografa con tomografa computada.25,26 Las caracters-
ticas principalmente responsables de las diferencias en la asig-
nacin de estatinas cuando se comparan las guas ACC/AHA
2013 con las guas ATP III son los modelos de evaluacin del
riesgo utilizados y el aumento potencial en la asignacin de
estatinas a la prevencin primaria de bajo riesgo.
Estimacin del riesgo absoluto:
una crtica comparativa
Las ecuaciones de la Cohorte Agrupada se introdujeron junto
a las guas ACC/AHA 2013 con las metas de ampliacin y di-
versidad tnica y geogrfica y la incorporacin del accidente
cerebrovascular como un resultado en el modelo de predic-
cin del riesgo.14 Desde su publicacin, varias caractersticas
 Nayor y Vasan Una comparacin de las guas para el tratamiento del colesterol
de las ecuaciones de la Cohorte Agrupada han sido critica-
das, incluyendo la sobreestimacin potencial del riesgo ab-
soluto, la dependencia de la edad cronolgica y la derivacin
en cohortes ms viejas con menor rendimiento en cohortes
ms contemporneas.
Estimacin del riesgo absoluto
La sobreestimacin del riesgo fue informada primero en las
guas ACC/AHA 2013 sobre la evaluacin del riesgo cardiovas-
cular, durante la validacin externa con datos de las ms con-
temporneas cohortes Multi-Ethnic Study of Atherosclerosis
(MESA) y Reasons for Geographic and Racial Differences
in Stroke (REGARDS), y con datos actualizados de ARIC y
FHS.14 Se han propuesto varias explicaciones para estos ha-
llazgos. Ante todo, se requiri un seguimiento de por lo menos
12 aos de las cohortes de derivacin para predecir con preci-
sin el riesgo a 10 aos. Por lo tanto, las tendencias duraderas
en el uso de estatinas, los procedimientos de revascularizacin
o el tratamiento de otros factores de riesgo como la hiper-
tensin y la diabetes mellitus pueden dar cuenta de las tasas
ms bajas de ECV observadas en cohortes ms contempor-
neas.27-29 La verificacin insuficiente de eventos clnicamente
relevantes en la validacin de cohortes puede tambin explicar
la aparente sobreestimacin. De hecho, cuando los investiga-
dores utilizaron datos de reclamos de Medicare para mejorar
la verificacin de resultados para el estudio REGARDS, de-
mostraron mejora de la performance de las ecuaciones de la
Cohorte Agrupada.28 Sin embargo, las preocupaciones acerca
de las ecuaciones de la Cohorte Agrupada se mantienen. La
sobreestimacin ha sido repetidamente demostrada en varias
cohortes modernas,24,30,31 y en por lo menos el Womens Health
Study, la sobreestimacin no fue explicada por diferencias en
el uso de estatinas, revascularizaciones o verificacin insu-
ficiente.27 A pesar de estos hallazgos, debera notarse que el
Womens Health Study fue un estudio de prevencin primaria
compuesto por voluntarias del estudio clnico.32 El riesgo ms
bajo observado en este estudio puede por lo tanto ser atribuible
parcialmente al efecto de voluntarias sanas.33
Aunque la investigacin adicional del desempeo de las
ecuaciones de la Cohorte Agrupada puede justificarse, vale
la pena considerar si otros modelos de previsin de riesgo
existentes se desempean mejor. Esta cuestin est subrayada
por la observacin de que cada una de las guas internaciona-
les destacadas aprueba un modelo de evaluacin del riesgo
diferente. Lamentablemente, las comparaciones sistemticas
entre los modelos de previsin de riesgo son raras, y los re-
sultados son frecuentemente conflictivos, dependiendo de las
caractersticas de las poblaciones estudiadas.34 El FRS, por
ejemplo, ha mostrado sobreestimar y subestimar el riesgo en
diferentes poblaciones.35
Caractersticas del desempeo del modelo
La calibracin y la discriminacin del modelo son 2 caracte-
rsticas que pueden usarse para evaluar el desempeo de los
modelos de previsin de riesgo. La calibracin, estimada por
la estadstica de Hosmer-Lemeshow, representa cun bien el
riesgo predicho se aproxima al riesgo observado. La discri-
minacin, medida por la estadstica c, se refiere a cun bien
el modelo distingue a aquellos que desarrollan la enferme-
dad de aquellos que no lo hacen.36 Con datos del Rotterdam
Study, los investigadores compararon el desempeo de las
ecuaciones de la Cohorte Agrupada, el FRS modificado y la
herramienta de evaluacin de riesgo SCORE y determinaron
47
que la calibracin fue similarmente mediocre en los tres mo-
delos, todos los cuales sobreestimaron significativamente el
riesgo del primer evento de ECV.24 Adems, la discrimina-
cin fue modesta (ms alta con la herramienta SCORE) entre
los tres modelos (la estadstica c en el rango de 0,67-0,77).24
De manera semejante, los investigadores de la cohorte MESA
evaluaron el desempeo de 3 diferentes ecuaciones del FRS,
el Reynolds Risk Score y la Cohorte Agrupada.31 Ellos en-
contraron una calibracin modesta para los 5 puntajes, con
discriminacin superior cuando se utiliz el Reynolds Risk
Score. A pesar de las diferencias demostradas en los estudios
de ms arriba, hay un pequeo consenso sobre el modelo de
previsin de riesgo ptimo.
Eleccin de variables y optimizacin de modelos
Los diferentes modelos de previsin de riesgo aprobados por
las guas de colesterol internacionales difieren poco en trmi-
nos de los factores de riesgo incluidos como pronstico, sien-
do el modelo QRISK2 notable por la incorporacin de varia-
bles adicionales. Podra considerarse en el futuro la evaluacin
del inters, oportunidad y factibilidad de establecer un marco
ms unificado para la estimacin global del riesgo cardiovas-
cular, quizs mediante el desarrollo de un modelo de previsin
de riesgo ECV internacional. Cuando los datos de las cohor-
tes internacionales estn combinados, puede optimizarse la
diversidad geogrfica, racial y tnica. La factibilidad de este
abordaje y la capacidad para calibrar el puntaje de riesgo para
diferentes pases fue demostrada recientemente.37 Por supues-
to, hay varios obstculos importantes para la bsqueda global
de este abordaje. Entre stos es primaria la falta de datos de
ciertos grupos geogrficos y tnicos. Por ejemplo, los as lla-
mados pases BRIC, Brasil, Rusia, India y China, representan
40% de la poblacin del mundo, pero los datos sobre evalua-
cin del riesgo cardiovascular en estos pases son limitados.38
Adems, es incierto el grado en que la evaluacin del riesgo
individual est afectada por caractersticas locales que no son
fciles de evaluar o integrar en los modelos de prediccin de
riesgo. Estos pueden incluir factores como el medio ambiente
local, dieta, clima, polucin atmosfrica, medio edilicio, fac-
tores culturales, disponibilidad de atencin de salud y ante-
cedentes genticos. Con el paciente representativo de nuestra
vieta clnica, observamos diferencias importantes en el riesgo
estimado utilizando cada uno de los 5 modelos de evaluacin
de riesgo. Aunque estas diferencias pueden ser parcialmente
explicadas por caractersticas especficas del modelo, los fac-
tores locales nicos pueden contribuir adicionalmente a varia-
ciones en la ponderacin de variables que podran complicar
la comparacin directa o la armonizacin de los distintos mo-
delos de evaluacin de riesgo.
Las tres caractersticas ms importantes de un modelo de
previsin de riesgo son las covariables incluidas, los resulta-
dos modelados y el horizonte de tiempo. La optimizacin de
cada una de estas caractersticas puede ayudar a refinar ms
las tcnicas de prediccin de riesgo. Como fue previamente
mencionado, la mayora de los modelos de prediccin de ries-
go existentes descansan ante todo en la edad, sexo, colesterol,
tensin arterial, estado del tratamiento antihipertensivo, dia-
betes mellitus y estado del hbito de fumar. Estas mediciones
individuales no dan cuenta de las variaciones de la exposicin
de toda la vida a los factores de riesgo. Puesto que los factores
de riesgo cardiovascular tradicionales llevan a la ateroescle-
rosis a travs de dcadas, es razonable pensar que la duracin
de la exposicin debe ser importante. Este abordaje es co-
48 Circulation Octubre 2016
mnmente utilizado para el hbito de fumar cigarrillos, que se
registran como paquetes-aos de exposicin y hay evidencia
para apoyar un abordaje similar con la hipertensin y la disli-
pidemia.39-41 Es tambin notable que la historia familiar de EC
prematura se incluye en el modelo QRISK2 y la modificacin
del FRS aprobado por la CCS, pero no est incorporada en
los modelos de ecuaciones SCORE ni la Cohorte Agrupada.
Ya que, como est citado por las guas CCS 2012, hay datos
que apoyan un riesgo aumentado 2 veces en aquellos con un
historia familiar de ECV prematura,21 es interesante que esta
variable no reuni los criterios para inclusin en ciertos mo-
delos. Quizs est relacionado con cmo se define la historia
familiar o se mide en las cohortes de derivacin. Aunque no
est incluida como una covariable en el modelo de las ecua-
ciones de la Cohorte Agrupada, las guas ACC/AHA 2013 in-
cluyeron la historia familiar de ECV prematura como un fac-
tor importante que puede considerarse cuando una decisin
de riesgo es incierta. Adems, para mejorar cmo se miden
factores de riesgo establecidos, el descubrimiento de factores
predictivos de riesgo nuevos (p. ej., utilizando datos genmi-
cos, biomarcadores y tcnicas de imgenes avanzadas) es un
rea de activa investigacin.
Los resultados ptimos para incluir en un modelo de previ-
sin de riesgo de ECV siguen siendo inciertos. En particular,
la inclusin del accidente cerebrovascular en las ecuaciones
de la Cohorte Agrupada ha sido cuestionada. Aunque la EC
y el infarto de miocardio son casi exclusivamente causados
por la enfermedad ateroesclertica, el accidente cerebrovascu-
lar es un trastorno heterogneo en el que la ateroesclerosis de
los grandes vasos da cuenta de 40% de la carga de enferme-
dad.42-44 Puesto que el colesterol plasmtico est directamente
relacionado slo con la ateroesclerosis de los grandes vasos,
utilizar los mismos factores de riesgo para predecir la EC y el
accidente cerebrovascular puede ser demasiado simplista. De
hecho, el LDL ha sido paradjicamente asociado con un riesgo
ms alto de accidente cerebrovascular hemorrgico en algunos
estudios.45 Adems, est bien descripto que la incidencia de
accidente cerebrovascular en los Estados Unidos vara amplia-
mente por regin geogrfica, dando lugar al trmino cinturn
de accidente cerebrovascular para referirse a la agrupacin de
11 estados del sudeste de EE.UU. con tasas de mortalidad por
accidente cerebrovascular ajustada por edad que son 10% ms
altas que el promedio nacional.46 Esta rea no est bien repre-
sentada en los 4 estudios de cohorte del National Heart, Lung,
and Blood Institute utilizados para la derivacin de la Cohorte
Agrupada. Por lo tanto, utilizar estas ecuaciones para estimar
el riesgo de accidente cerebrovascular en el cinturn de acci-
dente cerebrovascular puede indudablemente resultar en una
subestimacin. Por ltimo, el accidente cerebrovascular afecta
de manera desproporcionada a la vejez, con 17% de todos los
pacientes con accidente cerebrovascular >85 aos de edad, un
grupo de edad que est infrarrepresentado en las cohortes de
descubrimiento.47 Por lo tanto, incluir el accidente cerebrovas-
cular como un resultado puede reducir la precisin del modelo
y podra contribuir adicionalmente al aumento de la pondera-
cin de la edad en el modelo de prediccin de riesgo.
Impacto de la edad en la evaluacin del riesgo absoluto
En efecto, el dramtico efecto de la edad sobre el riesgo esti-
mado es una crtica adicional a las ecuaciones de la Cohorte
Agrupada, sin embargo tales efectos de la edad se observan
en cierta medida en todos los modelos de previsin de riesgo
mencionados previamente. Con las ecuaciones de la Cohorte
Agrupada, muchos adultos mayores pueden exceder el 7,5%
del umbral de riesgo estimado de ECV AS a 10 aos incluso
en ausencia de hbito de fumar, diabetes mellitus, hiperten-
sin o dislipidemia.48 Esta caracterstica es parcialmente un
resultado de la comnmente usada ventana de tiempo de 10
aos para prediccin del riesgo. La tasa absoluta de eventos
aumenta con la edad, como lo har el riesgo predicho. Por
lo tanto, los abordajes que son independientes de la edad
cronolgica tales como estimar la edad cardiovascular o el
riesgo de vida son alternativas atractivas porque la preven-
cin primaria de la ECV AS durante el curso de la vida, como
opuesta a la ventana de 10 aos de duracin, es el objetivo l-
timo. Reflejando este concepto, las ecuaciones de la Cohorte
Agrupada proveen un riesgo estimado de vida para individuos
de 20 a 59 aos de edad, y las guas CCS 2012 aprueban el
uso de edad del corazn en la toma de decisiones clnicas. Sin
embargo, se requiere investigacin adicional para determinar
cmo aplicar mejor estas evaluaciones en la atencin de ruti-
na y desarrollar una base probatoria para intervenciones im-
pulsadas por tales estimaciones.
Umbrales para la iniciacin de tratamiento
con estatinas
Ya sea un resultado de mejora de la precisin o una sobre-
estimacin del riesgo absoluto, las ecuaciones de la Cohorte
Agrupada explican parcialmente el aumento de adultos ele-
gibles para estatinas con las guas ACC/AHA 2013. Sin em-
bargo, otro factor crucial es la decisin de bajar el umbral al
cual debera considerarse el tratamiento con estatinas de pre-
vencin primaria para un riesgo absoluto a 10 aos estimado
de ECV AS 7,5%. De hecho, ste es el umbral ms bajo uti-
lizado por las guas internacionales revisadas aqu. El estado
de alto riesgo fue definido como un riesgo a 10 aos estimado
de EC >20% por las guas ATP III, ECV fatal 5% por cien-
to (equivalente a 15% para eventos no fatales) por las guas
ESC/EAS 2011, ECV 10% por las guas NICE, y 20% por
las guas CCS 2012. Debera notarse que puesto que los re-
sultados incluidos en la herramienta de evaluacin de riesgo
QRISK2 aprobadas por las guas NICE incluyen diagnsticos
ms suaves como angor o accidente isqumico transitorio, el
riesgo estimado de 10% por este clculo es probable que sea
cualitativamente similar al 7,5% de umbral de riesgo absoluto
de eventos de accidente cerebrovascular e infarto de miocar-
dio graves utilizado por las guas ACC/AHA 2013. Adems, la
decisin de bajar el umbral al 7,5% es apoyada por evidencia
reciente que demuestra que los beneficios del tratamiento con
estatinas en estudios de prevencin primaria incluyen aque-
llos con relativamente bajo riesgo y muy pequeas tasas de
efectos adversos en los metaanlisis de estudios de estatinas
que incluyen 170.000 participantes.49 En un metaanlisis de la
Cholesterol Treatment Trialists Collaboration, el tratamiento
con estatinas en gente con bajo riesgo (<10%) de ECV dio
como resultado una reduccin absoluta de eventos de ECV
mayores del 11 por 1000 durante cinco aos por cada 39 mg/dl
de reduccin de LDL, lo cual excedi grandemente cualquier
riesgo observado de tratamiento con estatinas.50 Una revisin
Cochrane de la eficacia de las estatinas en la prevencin pri-
maria de manera similar encontr que el nmero necesario a
tratar para prevenir un evento de ECV adverso fue de 167 para
aquellos con un riesgo a 5 aos de <5% y de 67 para aquellos
con un riesgo a 5 aos estimado de 5% a 10%.51 Por otra parte,
utilizando modelado con microsimulacin, Pandya y colegas52
 Nayor y Vasan Una comparacin de las guas para el tratamiento del colesterol
demostraron recientemente que el umbral de 7,5% es costo-
efectivo, con una proporcin de costo-efectividad incremental
de $37.000 por ao ganado ajustado por calidad.
Adems de aumentar el nmero de adultos elegibles para
estatinas en los Estados Unidos, otra consecuencia importante
de la disminucin del umbral de tratamiento es una reduccin
en la proporcin de individuos considerados de riesgo inter-
medio, que disminuira de 32% a 12% con la implementa-
cin plena de las guas ACC/AHA 2013.53 El tratamiento ms
apropiado para individuos de riesgo intermedio es, por defi-
nicin, menos cierto; por consiguiente, el juicio clnico y los
estudios adicionales han sido histricamente promovidos para
definir las recomendaciones de tratamiento en este grupo. Se
ha enfocado un significativa atencin en el desarrollo y vali-
dacin de biomarcadores en sangre e imgenes para mejorar
la precisin del riesgo estimado para estos individuos. Con la
disminucin del umbral de tratamiento, las guas ACC/AHA
2013 estn proponiendo que la evidencia reciente, revisada
ms arriba, apoya el uso de tratamiento con estatinas en la
mayora de los adultos que estuvieron previamente en la cate-
gora de riesgo intermedio y por lo tanto que el grupo de indi-
viduos en quienes el equilibrio en relacin con el tratamiento
ms adecuado ha disminuido.
Las guas internacionales que hemos revisado aprueban
fundar las decisiones de tratamiento en el riesgo de ECV ab-
soluto estimado. Sin embargo, publicaciones recientes han
sugerido potenciales modificaciones de estos mtodos. Navar-
Boggan y colegas54 han demostrado recientemente el beneficio
potencial de utilizar umbrales de riesgo a 10 aos especficos
por edad y sexo para guiar el tratamiento, incluyendo elevar el
umbral de tratamiento para adultos de 66 a 75 aos de edad a
10% en las mujeres y 15% en los hombres. Alternativamente,
Ridker y colegas55 han propuesto un algoritmo hbrido que in-
corporara datos de estudios clnicos dentro del algoritmo de
prevencin primaria, aunque la superioridad de esta estrategia
es incierta.56 Estas estrategias justifican investigacin adicio-
nal para determinar si pueden utilizarse para mejorar futuras
guas de colesterol.
Objetivos teraputicos para el tratamiento de
disminucin de lpidos
Otra importante modificacin introducida por las guas
ACC/AHA 2013 fue la remocin de los objetivos de trata-
miento especficos para el tratamiento de disminucin de lpi-
dos. En la explicacin de su base racional, el comit de la gua
refiri la ausencia de datos de estudios clnicos que indiquen
qu objetivos precisos deberan ser, la falta de un beneficio
probado para un objetivo versus otro, la incapacidad para dar
cuenta de los efectos adversos o esforzarse para lograr una
meta dada, y la preocupacin de que las estrategias basadas en
objetivos puedan dar como resultado un infratratamiento con
estatinas o un sobretratamiento con no estatinas para alcanzar
esos objetivos.11 Adicionalmente, hay pequeas pero signifi-
cativas diferencias entre la estimacin de la concentraciones
de LDL con la frmula de Friedewald y mediciones directas.57
As, con una estrategia de tratar segn un objetivo, el mismo
paciente puede tener diferentes recomendaciones dependiendo
del estudio de LDL utilizado. Por otra parte, los crticos de
este abordaje agnstico del objetivo han argumentado que
los objetivos del tratamiento son valiosos en la prctica clnica
y que sirven para reforzar la conducta positiva del paciente y
los cambios del estilo de vida y brindar a los pacientes y a sus
49
mdicos metas y mediciones tangibles.58 Adems, quitar los
objetivos del tratamiento hace difcil para los pacientes me-
jorar su perfil de riesgo (por medios no farmacolgicos) de
manera suficiente para no justificar ms la farmacoterapia.
Comenzar una medicacin preventiva sin la posibilidad de
discontinuar la medicacin en el futuro puede ser un desafo
filosfico desde una perspectiva de la salud pblica porque
esto esencialmente medicaliza a una gran proporcin de la co-
munidad mientras quita nfasis a la importancia potencial de
modificaciones en el estilo de vida.
Aunque las ms recientes guas NICE de manera semejan-
te acaban con los objetivos del tratamiento, las ltimas guas
ESC/EAS y CCS continan aprobando las estrategias de tratar
segn un objetivo.16,18 En las guas ESC/EAS y CCS, la justifi-
cacin para continuar con el uso de los objetivos de colesterol
incluye una cantidad de estudios de estatinas de prevencin
primaria y secundaria demostrando mejora de los resultados
con el descenso ms intensivo de LDL.49,50,59-62 Sin embargo,
ninguno de estos estudios utiliz objetivos de LDL especfi-
cos para provocar ajustes de la dosis de la medicacin, as los
objetivos de LDL son extrapolados de estos estudios. Esta es
un rea altamente polmica en la que los datos de los estu-
dios controlados aleatorizados y la prctica clnica diaria se
muestran en conflicto. Se necesitan tcnicas de investigacin
innovadoras para evaluar los efectos de las estrategias de tratar
segn un objetivo sobre los resultados del paciente, incorpo-
rando los efectos a corto plazo de la disminucin de lpidos y
los efectos a largo plazo relativos al bienestar del paciente y
que alienten conductas de estilo de vida saludables.
Dos desarrollos desde la publicacin de las guas ACC/AHA
2013 pueden complicar adicionalmente el abordaje de obje-
tivo agnstico. El primero es la publicacin de los resulta-
dos del Improved Reduction of Outcomes: Vytorin Efficacy
International Trial (IMPROVE-IT), que demostr una reduc-
cin del riesgo absoluto del 2% de eventos de ECV con ezeti-
mibe aadido al tratamiento con estatinas en pacientes despus
de un infarto de miocardio.10 Los individuos que recibieron la
combinacin de simvastatina y ezetimibe tuvieron promedio
ms bajo de niveles de LDL (53,2 versus 69,9 mg/dl), sugi-
riendo que ms bajo es mejor para el colesterol LDL, por lo
menos en el contexto de la prevencin secundaria. El segun-
do desarrollo es la reciente aprobacin por la Food and Drug
Administration de EE.UU. de 2 drogas de la nueva clase de
inhibidores de la proprotein-convertasa subtilisina/kexin tipo
9. Mientras los estudios que evalan el impacto en los resul-
tados sobre la ECV severa estn en curso, estas drogas pare-
cen ser seguras y eficaces en el descenso de LDL.63 El estudio
IMPROVE-IT fue el primero en demostrar el beneficio de aa-
dir una medicacin no estatina en pacientes ya tratados con
estatinas para prevencin secundaria. A medida que proliferan
las opciones de medicaciones no estatinas para el descenso de
LDL, los comits de guas futuras tendrn la tarea de evaluar si
podra estar justificado un retorno a los objetivos de tratamien-
to de LDL (por lo menos en ciertas circunstancias) para guiar
la adicin de estas nuevas opciones farmacolgicas en ciertos
pacientes de alto riesgo ya tratados con estatinas.64
Abordaje de prevencin primaria para aquellos
con diabetes mellitus o ERC
A pesar de las diferencias en el lenguaje utilizado y los deta-
lles acerca de la dosis de estatinas sugerida, las guas interna-
cionales generalmente estn de acuerdo sobre el abordaje a
50 Circulation Octubre 2016
la prevencin primaria en aquellos con diabetes mellitus (la
Tabla 2 brinda detalles). Las diferencias notables pertenecen
mayormente al tratamiento de los pacientes <40 aos de edad,
en quienes hay escasa evidencia de lo apropiado del tratamien-
to con estatinas para la prevencin primaria de la ECV.
El acuerdo entre las guas es menos uniforme para el tra-
tamiento de individuos con ERC. Las guas ACC/AHA 2013
son las nicas entre las guas internacionales revisadas en no
considerar la presencia de ERC para conferir alto riesgo. Las
guas ESC/EAS 2011 y CCS 2012 caracterizan a los pacien-
tes con ERC como de alto o muy alto riesgo y recomiendan
tratamiento con estatinas para lograr los objetivos apropiados
de LDL.16,18 Las guas NICE 2014 recomiendan comenzar con
atorvastatina 20 mg para todos los pacientes con ERC.17 Los
documentos ACC/AHA 2013, ESC/EAS 2011, NICE 2014 y
CCS 2012 estn de acuerdo en que no hay evidencia suficiente
para apoyar recomendaciones especficas para los pacientes
con enfermedad renal de estadio terminal que reciben hemo-
dilisis regular. Aunque las guas ACC/AHA 2013 son las
nicas entre las guas internacionales revisadas en no tratar a
todos los individuos con ERC como de alto riesgo, utilizando
datos del estudio REGARDS, Colantonio y colegas65 demos-
traron que solamente el 8% de los individuos con ERC que
tienen de 50 a 79 aos de edad no calificara para la conside-
racin de tratamiento con estatinas sobre las bases de las guas
ACC/AHA 2013. Por lo tanto, es incierto si esta distincin en-
tre las guas ACC/AHA 2013 y otras guas realmente afecta las
recomendaciones a nivel individual.
Otras guas de EE.UU. recientes
Desde la publicacin de las guas ACC/AHA 2013, la US
Preventive Services Task Force (USPSTF)48 y la National
Lipid Association (NLA)66 han publicado recomendaciones
para la prevencin de ECV. El acuerdo entre las recomenda-
ciones del proyecto de declaracin de la USPSTF (que apunta
a la prevencin primaria) y las guas ACC/AHA 2013 es en
general fuerte. Las recomendaciones de la USPSTF apoyan el
uso de las ecuaciones de la Cohorte Agrupada para la evalua-
cin del riesgo absoluto y sugieren aparear la intensidad del
tratamiento con estatinas al riesgo absoluto (como opuesto al
abordaje de tratamiento segn el objetivo de otras guas). Una
notable diferencia, sin embargo, es que las recomendaciones
de la USPSTF requieren individuos que tengan un riesgo a 10
aos de ECV AS de 10% (como opuesto a 7,5%) y por lo
menos 1 factor de riesgo cardiovascular para calificar al trata-
miento con estatinas. Para aquellos con un riesgo estimado de
ECV AS a 10 aos de 7,5% a 10%, la USPSTF declara que las
estatinas a dosis bajas a moderadas pueden considerarse para
individuos con factores de riesgo adicionales o despus de
una discusin con el paciente acerca de la reduccin del ries-
go absoluto relativamente pequea esperada en este grupo.48
Esta distincin entre la declaracin de la USPSTF y las guas
ACC/AHA 2013 destaca varios temas importantes previamen-
te elevados en esta revisin, incluyendo la incertidumbre de
los mtodos de prediccin de riesgo actuales y las dificultades
para balancear los considerables costos y los efectos adversos
potenciales asociados con el uso de estatinas con la pequea
reduccin de riesgo absoluto en individuos con un riesgo de
ECV AS absoluto a 10 aos de <10%.
En contraste, las guas de la NLA difieren sustancialmente
de las guas ACC/AHA 2013.66 La NLA enfatiza el conteo de
los factores de riesgo como opuestos a la evaluacin del riesgo
absoluto como medios primarios de asignacin de categora
de riesgo, con el riesgo absoluto a ser calculado solamente en
aquellos con dos factores de riesgo mayores. Las guas de la
NLA consideran que el alto riesgo es un riesgo de ECV AS
estimado a 10 aos de 15% (utilizando las ecuaciones de la
Cohorte Agrupada). Adems, las guas de la NLA tambin
aprueban una estrategia de tratamiento segn el objetivo y
apoyan el uso de objetivos de tratamiento basados en no-HDL
como opuesto al LDL. Con estas caractersticas, las guas de
la NLA son ms similares a las guas ATP III, ESC/EAS 2011
y CCS 2012 que a las guas ACC/AHA 2013.
Resumen
Las guas ACC/AHA 2013 para el tratamiento del colesterol
hacen varios cambios notables con respecto a las antiguas
guas ATP III. De estos, los tres de mayor impacto son la in-
troduccin de las ecuaciones de la Cohorte Agrupada como la
herramienta de evaluacin de riesgo preferida, y disminuir el
umbral de riesgo para la consideracin de estatinas en los cua-
dros de prevencin primaria (comenzando con una discusin
mdico-paciente) a un riesgo de ECV AS absoluto a 10 aos
de 7,5%, y quitar los objetivos del tratamiento del colesterol.
Despus de revisar varias guas internacionales destacadas,
observamos una falta de consenso sobre el abordaje ptimo
de la evaluacin del riesgo, umbrales de tratamiento, o el uso
de objetivos de colesterol entre estas guas. Como resultado,
las recomendaciones para la prevencin primaria del trata-
miento de disminucin de lpidos para un individuo varan de
acuerdo a cul pauta se sigue, como se ilustra por medio de
la vieta clnica. Estas observaciones subrayan la importancia
de investigacin adicional enfocada a refinar los modelos de
prediccin del riesgo y determinar las estrategias ptimas para
controlar y ajustar el tratamiento mdico.
Fuentes de fondos
Dr Nayor fue apoyado por un subsidio de entrenamiento T32-
HL007604 de los National Institutes of Health y del Clinical Skills
Development Core Training National Heart, Lung, and Blood
Institute U10HL110337. Dr. Vasan fue apoyado por contratos del
National Heart, Lung, and Blood Institutes Framingham Heart Study
N01-HC-25195 y HHSN268201500001I.
Declaracin de intereses
Ninguno.
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