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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
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
deaths are still attributable to ischemic heart disease and stroke.1 and weighs 180 lb (81.6 kg); his body mass index is 26.6 kg/
These conditions also account for a large proportion of disabil- m2; his blood pressure is 144/86 mmHg; and his fasting lipid
ity and global healthcare costs.2,3 Elevated blood cholesterol is profile reveals a total serum cholesterol of 195 mg/dL, low-
among the most prevalent modifiable cardiovascular risk factors, density lipoprotein (LDL) cholesterol (LDL-C) of 125 mg/
with medical therapies proven to reduce both CVD incidence dL, high-density lipoprotein cholesterol (HDL-C) of 50 mg/
and related mortality.410 Therefore, clinical practice guidelines dL, and triglycerides of 100 mg/dL (to convert from mg/dL to
addressing the treatment of blood cholesterol have a tremen- mmol/L, multiply LDL-C or HDL-C by 0.0259 and multiply
dous potential impact on population health and related health- triglycerides by 0.0113).
care costs. The most recent US guidelines on the treatment of
blood cholesterol11 contain important changes from the previ- 2013 American College of Cardiology/
ous version.12,13 In this review, we aim to summarize the rec- American Heart Association Guideline
ommendations from the most recent US cholesterol guideline,
highlighting specific changes from the previous version, and in Methodology
parallel compare it with other leading international guidelines. The 2013 American College of Cardiology/American Heart
Association Guideline on the Treatment of Blood Cholesterol
to Reduce Atherosclerotic Cardiovascular Risk in Adults11
Guidelines for the Treatment of Blood Cholesterol
(2013 ACC/AHA guideline) was commissioned to reflect new
Clinical Vignette evidence since the previous Adult Treatment Panel III (ATP
To demonstrate differences between the various guidelines, III) guidelines were last updated in 2004.12,13 Whereas previ-
we refer to a representative patient (Figure): Consider a 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 Cohort equations were derived with data from 4 National
the focus to atherosclerotic CVD (ASCVD), including CHD, Heart, Lung, and Blood Institutesponsored cohort studies
stroke, and peripheral arterial disease. The 2013 ACC/AHA the Atherosclerosis Risk in Communities (ARIC) study, the
task force used a new approach to assess available evidence, Cardiovascular Health Study (CHS), the Coronary Artery
focusing on randomized, controlled trials and systematic Risk Development in Young Adults (CARDIA) study, and the
reviews and meta-analyses of randomized, controlled trials. Framingham Heart Study (FHS; including original and off-
Furthermore, the new guideline differed from the previous spring cohorts)with adjudicated clinical outcomes, includ-
iterations in its intended scope. Whereas the ATP III guide- ing myocardial infarction, CHD death, and fatal or nonfatal
lines included a comprehensive topical review and recommen- stroke.14 The risk factors meeting the criteria for inclusion in
dations for laboratory evaluation, clinical diagnosis, lifestyle the multivariable model were age, sex, total cholesterol, HDL-
interventions, and drug therapy, the 2013 ACC/AHA guide- C, systolic blood pressure, antihypertensive treatment status,
line focused on answering 3 critical questions: (1) What is diabetes mellitus, and current smoking status. Of these vari-
the evidence for LDL-C and nonHDL-C goals in secondary ables, only diabetes mellitus was not included in the modified
prevention of ASCVD? (2) What is the evidence for LDL-C FRS endorsed by the ATP III guidelines. Different multivari-
and nonHDL-C goals in primary prevention of ASCVD? able models were constructed for white and black individuals,
(3) What are the effectiveness and safety of lipid-modifying and caution was recommended when these equations were
drugs in the primary and secondary prevention of ASCVD?11 applied to other races and to adults outside the age range of
An independent contractor selected the relevant studies to be 40 to 79 years.
reviewed for each critical question according to prespecified
criteria. This methodology was designed to reduce bias and to Treatment Recommendations
ensure that lower-quality studies were not considered when The 2013 ACC/AHA guideline recommended treatment with
the recommendations were formulated. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors
(statins) for 4 categories of individuals: (1) secondary pre-
Risk Assessment Model vention for those with established ASCVD, (2) primary pre-
A new tool for global risk assessment was introduced with vention of ASCVD for those with LDL-C 190 mg/dL, (3)
the 2013 ACC/AHA guideline.11 The previous guidelines rec- primary prevention of ASCVD for individuals with diabetes
ommended using a modified Framingham Risk Score (FRS) mellitus and LDL-C of 70 to 189 mg/dL, and (4) primary pre-
to estimate the 10-year risk of myocardial infarction or CHD vention of ASCVD for those without diabetes mellitus, with
death. Criticisms of this model included the absence of stroke LDL of 70 to 189 mg/dL, but with an estimated 10-year abso-
as an outcome and a lack of racial, ethnic, and geographic lute risk of 7.5% as assessed by the Pooled Cohort equa-
diversity in the derivation population. In response, the Pooled 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 would be considered at intermediate risk on the basis of an
on a detailed risk discussion between patient and clinician estimated 10-year absolute risk of CHD of 10%. Hence, his
before the initiation of statin therapy.15 This clinician-patient LDL-C target would be <130 mg/dL, and given his current
discussion should include an assessment of the potential ben- LDL-C of 125 mg/dL, he would not receive statin therapy.
efit, possible adverse effects and drug-drug interactions, life- Notably, a white man was used for our representative clini-
style changes, management of other risk factors, and of course cal vignette. The difference in estimated risk between the Pooled
patient preferences. Additionally, other factors that might Cohort equations and the FRS would be more pronounced if
affect net risk reclassification could be used to further inform a black woman, for example, had the same risk factor profile.
the treatment decision; these include LDL-C 160 mg/dL or With the Pooled Cohort equations, she would have an estimated
evidence of genetic dyslipidemia, elevated lifetime risk, fam- 10-year ASCVD risk of 7.4%, which is considerably higher than
ily history of premature CVD, blood levels of high-sensitivity the 2% 10-year CHD risk estimated by the FRS.
C-reactive protein 2.0 mg/L, ankle-brachial index <0.9, or
abnormal coronary artery calcium score (300 Agatston units 2011 European Society of Cardiology/
or 75th percentile for age, sex, and ethnicity). Individuals at European Atherosclerosis Society Guidelines
intermediate risk (10-year absolute risk of 5%7.4%) or low
risk (10-year absolute risk <5%) could also be considered for Methodology
statin therapy on the basis of patient preferences or perceived The European Society of Cardiology/European Atherosclerosis
benefit based on additional factors such as those listed above. Society Guidelines for the Management of Dyslipidaemias16
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Instead of setting specific LDL-C targets, the 2013 ACC/ (2011 ESC/EAS guidelines) are a comprehensive document
AHA guideline essentially suggested a fixed dose (or inten- addressing cardiovascular risk assessment, laboratory evalua-
sity) of statin for each risk category, with intended LDL-C tion, lifestyle modifications, drug treatment, and the approach
reductions of 30% to 49% and 50% for moderate- and high- to specific clinical settings such as familial dyslipidemias. The
intensity statins, respectively. The authors also suggested that ESC/EAS task force based its findings on a comprehensive
nonstatin medications could be considered for those at high review of the literature in which greater confidence was placed
risk (secondary prevention, diabetes mellitus, LDL-C 190 in the results of randomized, controlled trials but was inclu-
mg/dL) if they are intolerant of the recommended dose of sive of all study designs.
statin or have an inadequate response to statins. Although spe-
cific LDL-C targets were not endorsed, the 2013 ACC/AHA Risk Assessment Model
guideline recommended monitoring of the plasma lipid levels Similar to the 2013 ACC/AHA guideline, the 2011 ESC/EAS
to ensure adherence, therapeutic response, and safety. guidelines supported the routine use of global cardiovascu-
In comparison, the ATP III guidelines recommended a lar risk assessment for all adults without established CVD but
treat-to-target strategy with specific LDL-C goals for each endorsed the use of the Systemic Coronary Risk Evaluation
risk group. For primary prevention, the LDL-C goal was set (SCORE) risk assessment tool. The SCORE tool, derived
at <100 mg/dL for high-risk individuals (10-year CHD risk by pooling data from cohort studies with participants in 12
>20%), <130 mg/dL for those at intermediate risk (10-year European countries, is designed to estimate the 10-year risk
risk CHD risk, 10%20%), and <160 mg/dL for low-risk of fatal CVD event.19 The decision to include only fatal out-
individuals (10-year CHD risk <10%). The LDL-C goal for come events was based on the assessment that fatal events are
secondary prevention or primary prevention of CVD in those more easily calibrated in different populations and are less
with diabetes mellitus was <100 mg/dL, with the option to likely than nonfatal events to be affected by local geographic
target <70 mg/dL for those at highest risk of CVD.12,13 variations in diagnosis and treatment.19 The total CVD event
In summary, the most important differences between the rate (including nonfatal events) has been shown to be 3-fold
2013 ACC/AHA guideline and the ATP III guidelines are the higher than the fatal CVD event rate.16 Variables included in
introduction of the Pooled Cohort equations, the elimination the SCORE risk model include age, sex, systolic blood pres-
of LDL-C treatment targets, and the lowering of the threshold sure, total cholesterol, and smoking status, and separate mod-
at which statins should be considered to an estimated 10-year els are used for low- and high-risk European countries.
absolute risk of 7.5%. The differences between these 2 docu-
ments are summarized in Table1. To provide further context Treatment Recommendations
for the 2013 ACC/AHA guideline, we next compare its rec- According to the 2011 ESC/EAS guidelines, patients are
ommendations with those from other leading international considered to be very high risk for documented CVD, type 2
guidelines, as outlined in Table2. diabetes mellitus, type 1 diabetes mellitus with target organ
damage, moderate to severe chronic kidney disease (CKD), or
Clinical Vignette estimated 10-year absolute risk of fatal CVD 10%. High-risk
With the Pooled Cohort equations, the patient in our clinical individuals are those with a 10-year risk of fatal CVD of 5%
vignette would have an estimated 10-year absolute ASCVD to 9.9% or marked elevations in risk factors such as familial
risk of 10.3%, and moderate- to high-intensity statin ther- dyslipidemia or severe hypertension. Moderate risk is defined
apy could be considered after a clinician-patient discussion as a 10-year risk of fatal CVD of 1% to 4.9%, and low risk is
of potential risk reduction, adverse effects, drug-drug inter- defined as an estimated 10-year risk of fatal CVD event <1%.
actions, and patient preferences. With the modified FRS Extrapolating from clinical trials, the task force recommended
endorsed by the ATP III guidelines, on the other hand, he 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 2001 ATP III Guidelines12 With 2004 Update13
Focus of primary prevention ASCVD, including CHD, stroke, and peripheral arterial disease CHD
Guideline scope Limited to 3 critical questions: evidence for cholesterol goals in Comprehensive document, including literature
secondary prevention, evidence for cholesterol goals in primary review, diagnosis and evaluation, treatment,
prevention, and effectiveness and safety of lipid-modifying drugs lifestyle changes, and special clinical settings
Evidence considered Randomized, controlled trials and meta-analyses of randomized, Inclusive systematic review
controlled trials
Risk assessment tool Pooled Cohort risk equations: Modified FRS:
End points: CHD death, nonfatal MI, fatal or nonfatal stroke End points: CHD death, nonfatal MI
Derivation sample: pooled data from 4 cohort studies Derivation sample: mostly white population of
Predictors selected in the multivariable model: age, sex, total European descent
cholesterol, HDL-C, systolic blood pressure, antihypertensive Predictors selected in the multivariable model:
treatment status, diabetes mellitus, and current smoking status age, sex, total cholesterol, HDL-C, systolic blood
Additional considerations: separate models created for men and pressure, antihypertensive treatment status, and
women and for whites and blacks current smoking status
Cholesterol treatment targets endorsed No Yes
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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 2014 National Institute for Health
mg/dL (3.0 mmol/L) for moderate risk, and <190 mg/dL (4.9 and Care Excellence Guidelines
mmol/L) for low risk. Therefore, the 2011 ESC/EAS guide-
lines differ from the 2013 ACC/AHA guideline in the choice Methodology
of risk assessment model, the estimated 10-year risk consid- The guidelines for lipid modification from the National
ered sufficient to warrant medical treatment, and the contin- Institute for Health and Care Excellence (NICE) in England
ued endorsement of specific LDL-C targets to guide therapy. were last updated in 2014.17 The NICE guidelines are similar
in scope to the 2013 ACC/AHA guideline, with recommenda-
Clinical Vignette tions for the primary and secondary prevention of CVD. Of
According to the SCORE risk assessment tool, our patient the international guidelines reviewed, the NICE guidelines are
has a 10-year estimated risk of CVD mortality of 5% if he noteworthy for the specificity of the drug recommendations
lives in a high-risk European country and would be consid- provided and for the extent to which cost-effectiveness analy-
ered at high risk. If he lives in a low-risk country, however, ses are used to justify the recommendations.
his 10-year estimated risk of CVD death would be 3%, and
he therefore would be considered at moderate risk. Regardless Risk Assessment Model
of his country of residence, statin treatment would be recom- The NICE guidelines support the use of the QRISK2 risk
mended, given the LDL-C targets of <100 mg/dL for high-risk assessment tool for global cardiovascular risk assessment in
and <115 mg/dL for moderate-risk individuals. 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 2013 ACC/AHA Guideline11 2011 ESC/EAS Guidelines16 2014 NICE Guidelines17 2012 CCS Guidelines18
Evidence considered Randomized, controlled trials Comprehensive literature Comprehensive literature Comprehensive literature
review review review
Risk assessment tool Pooled Cohort equations SCORE risk assessment tool QRISK2 risk assessment tool FRS for total CVD
End points CHD death, nonfatal MI, fatal CHD death or fatal stroke CHD death, CHD (MI or CHD death, MI, coronary
or nonfatal stroke (total CVD events is 3-fold angina), stroke, or transient insufficiency, angina,
higher than fatal event rate) ischemic attack ischemic or hemorrhagic
stroke, transient ischemic
attack, peripheral artery
disease, heart failure
Derivation sample Pooled data from 4 cohorts Pooled data from 12 British population, updated Mostly white population of
European countries annually European descent
Predictors selected in the Age, sex, total cholesterol, Age, sex, total cholesterol, Age, sex, total cholesterol, Age, sex, total cholesterol,
multivariable model HDL-C, systolic blood systolic blood pressure, and HDL-C, systolic blood HDL-C, systolic blood
pressure, antihypertensive smoking status pressure, hypertension pressure, antihypertensive
treatment status, diabetes (separate models for high- treatment status, diabetes treatment status, diabetes
mellitus, and smoking status mellitus, smoking status, mellitus, and smoking status
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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 also recommended for those with diabetes mellitus and for
myocardial infarction), stroke, or transient ischemic attack; is secondary prevention, with a goal of <70 mg/dL (1.8 mmol/L)
specifically calibrated to the British population; and is updated considered to be optional for those at highest risk.
annually. Compared with the Pooled Cohort equations and
SCORE risk assessment tool, the QRISK2 multivariable model Clinical Vignette
includes additional risk factors such as ethnicity, family his- The patient in our clinical vignette has an estimated 10-year
tory of premature CHD, socioeconomic deprivation, body mass risk of total CVD of 16.6% according to the FRS and would
index, rheumatoid arthritis, CKD, and atrial fibrillation (in addi- be characterized as intermediate risk. The LDL-C target for
tion to age, sex, systolic blood pressure, total cholesterol, HDL- the intermediate-risk group is <130 mg/dL. Therefore, he
C, hypertension treatment status, diabetes mellitus, and smoking would not be recommended to receive statin therapy.
status, which are included in the Pooled Cohort equations).20
Comparison of International Guidelines
Treatment Recommendations The 2013 ACC/AHA guideline differs substantially from its
Similar to the 2013 ACC/AHA guideline, the 2014 NICE previous version, the ATP III guidelines, and other leading
guidelines do not endorse a treat-to-target strategy. Instead, international guidelines. The effects of these changes were
statin therapy is recommended for primary prevention in indi- illustrated by our representative clinical vignette, in which the
viduals with type 2 diabetes mellitus or those without diabetes recommendations for initiating statin therapy for a 60-year-old
mellitus but with an estimated 10-year absolute CVD risk of man with modest cardiometabolic risk factors varied accord-
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10%. Statin therapy is also recommended for patients with ing to the guideline followed (Figure). The leading interna-
type 1 diabetes mellitus who are >40 years of age with a dis- tional guidelines included in this review differ in 3 key areas:
ease duration of >10 years or with evidence of target organ the suggested risk assessment model (component risk factors
damage. Atorvastatin 20 mg daily is recommended for pri- and outcome evaluated), the threshold of risk considered suf-
mary prevention, and atorvastatin 80 mg daily is used for sec- ficient to warrant initiating medical therapy, and the decision
ondary prevention. In patients with CKD, 20 mg atorvastatin of whether to use a treat-to-target strategy.
is suggested for both primary and secondary prevention.
Predicted Impact of Changes Proposed
Clinical Vignette
The patient in our clinical vignette has an estimated 10-year
by the 2013 ACC/AHA Guideline
Dyslipidemia and cardiometabolic risk factors are highly
CVD risk of 10.4% with the QRISK2 model and would thus
prevalent in the population; therefore, changes to cholesterol
meet the criteria for statin therapy as primary prevention.
treatment guidelines will affect the treatment recommenda-
tions for many people. Using data from the National Health
2012 Canadian Cardiovascular and Nutrition Examination Surveys (NHANES), Pencina and
Society Guidelines colleagues demonstrated that 13 million American adults
Methodology and Risk Assessment Model would be newly eligible for statin therapy with full imple-
The Canadian Cardiovascular Society (CCS) guidelines for mentation of the 2013 ACC/AHA guideline.23 The increase in
the diagnosis and treatment of dyslipidemia for the prevention statin eligibility was attributable primarily to a higher propor-
of CVD in adults were last updated in 2012 (2012 CCS guide- tion of individuals 60 to 75 years of age meeting criteria for
lines).18 The 2012 CCS guidelines recommend using the FRS treatment, which grew from 47.8% with the ATP III guidelines
for total CVD events to estimate the 10-year absolute risk. to 77.3% with the 2013 ACC/AHA guideline. The true impact
These guidelines also suggest doubling the estimated absolute of the 2013 ACC/AHA guideline is likely to be overestimated
risk for individuals with a family history of premature CVD by these calculations, which assumed that all individuals in a
on the basis of evidence of a 2-fold increase in CVD risk for statin benefit group would be treated with statins and there-
FHS participants with a family history of premature CVD.21 fore did not consider the effect of a clinician-patient discus-
The authors of the 2012 CCS guidelines advise considering sion (emphasized by the new guidelines specifically) of the
cardiovascular age in addition to estimated 10-year absolute risks and benefits of statin initiation. Nevertheless, the 2013
risk when discussing lipid-lowering treatment with patients. ACC/AHA guideline is predicted to result in a higher number
Cardiovascular age and heart age may be easier concepts of statin-eligible individuals in the United States.
for patients to understand and may thereby facilitate shared The overall impact of a larger proportion of the popula-
decision making between patient and provider.22 tion receiving statin therapy is uncertain. Although overtreat-
ment is a concern,24 several recent studies have suggested
Treatment Recommendations that the 2013 ACC/AHA guideline aligns more closely than
The 2012 CCS guidelines endorse a treat-to-target strategy the ATP III guidelines with coronary atherosclerotic burden,
with primary prevention LDL-C targets of <75 mg/dL (2.0 as assessed by coronary artery calcium score and computed
mmol/L) for high-risk patients (10-year absolute risk 20%, tomography angiography.25,26 The features primarily responsi-
CKD, or high-risk hypertension), <130 mg/dL (3.5 mmol/L) ble for the differences in statin allocation when the 2013 ACC/
for intermediate-risk individuals (10-year absolute risk, 10% AHA guideline is compared with the ATP III guidelines are
19%), and <190 mg/dL (5 mmol/L) for those at low risk (10- the risk assessment models used and the potential increase in
year absolute risk <10%). A target LDL-C of <75 mg/dL is statin assignment to lower-risk primary prevention.
Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1801

Absolute Risk Estimation: A well the model distinguishes those who develop the disease
Comparative Critique from those who do not.36 With data from the Rotterdam Study,
The Pooled Cohort equations were introduced alongside the investigators compared the performance of the Pooled Cohort
2013 ACC/AHA guideline with the goals of broadening eth- equations, the modified FRS, and the SCORE risk assess-
nic and geographic diversity and incorporating stroke as an ment tool and determined that calibration was similarly poor
outcome in the risk prediction model.14 Since their publica- among the 3 models, all of which significantly overestimated
tion, several features of the Pooled Cohort equations have the risk of first CVD event.24 Furthermore, discrimination was
been criticized, including potential overestimation of absolute modest (highest with the SCORE tool) among the 3 models
risk, dependence on chronological age, and derivation in older (c statistics ranging from 0.670.77).24 Similarly, investigators
cohorts with reduced performance in more contemporary from the MESA cohort evaluated the performance of 3 dif-
cohorts. ferent FRSs, the Reynolds Risk Score, and the Pooled Cohort
equations.31 They found modest calibration for the 5 scores,
Absolute Risk Estimation with superior discrimination when the Reynolds Risk Score
Overestimation of risk was first reported in the 2013 ACC/ was used. Despite the differences demonstrated in the above
AHA guideline on the assessment of cardiovascular risk, dur- studies, there is little consensus on the optimal risk prediction
model.
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)
Choice of Variables and Optimizing Models
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The different risk prediction models endorsed by the inter-


cohorts, and with updated data from ARIC and FHS.14 Several
national cholesterol guidelines vary little in terms of the risk
explanations for these findings were proposed. Foremost, a
factors included as predictors, with the QRISK2 model being
follow-up of at least 12 years was required for the derivation
noteworthy for incorporating additional variables. Future
cohorts to accurately predict 10-year risk. Therefore, secular
consideration could be given to assessing the desirability,
trends in statin use, revascularization procedures, or treat-
appropriateness, and feasibility of establishing a more uni-
ment of other risk factors such as hypertension and diabetes
fied framework for estimating cardiovascular risk globally,
mellitus may account for the lower rates of CVD observed in
perhaps by developing an international CVD risk prediction
more contemporary cohorts.2729 Underascertainment of clini-
model. When data from international cohorts are combined,
cally relevant events in the validation cohorts may also explain
geographic, racial, and ethnic diversity can be optimized. The
the apparent overestimation. In fact, when investigators used feasibility of this approach and the ability to calibrate a risk
Medicare claims data to improve outcome ascertainment for score to different countries were recently demonstrated.37 Of
the REGARDS study, they demonstrated improved perfor- course, there are several important hurdles to pursuing this
mance of the Pooled Cohort equations.28 However, concerns approach globally. Primary among these is the lack of data
about the Pooled Cohort equations remain. Overestimation has for certain geographic and ethnic groups. For example, the
repeatedly been demonstrated in several modern cohorts,24,30,31 so-called BRIC countries of Brazil, Russia, India, and China
and in at least the Womens Health Study, the overestimation represent 40% of the worlds population, but data on car-
was not explained by differences in statin use, revascular- diovascular risk assessment in these countries are limited.38
izations, or underascertainment.27 Despite these findings, it Furthermore, the degree to which individual risk assessment is
should be noted that the Womens Health Study was a primary affected by local characteristics that are not easily evaluated or
prevention trial composed of clinical trial volunteers.32 The integrated into risk prediction models is uncertain. These may
lower risk observed in this study might therefore be partially include factors such as local environment, diet, climate, air
attributable to a healthy volunteer effect.33 pollution, built environment, cultural factors, availability of
Although further investigation into the performance of health care, and genetic background. With the representative
the Pooled Cohort equations may be warranted, it is worth patient in our clinical vignette, we observed important differ-
considering whether other existing risk prediction models ences in the estimated risk using each of the 5 risk assess-
perform better. This question is underscored by the observa- ment models. Although these differences could be partially
tion that each of the leading international guidelines endorses explained by specific model characteristics, the unique local
a different risk assessment model. Unfortunately, systematic factors may further contribute to variations in the weighting of
comparisons between risk prediction models are rare, and variables, which could complicate direct comparison or har-
results are often conflicting, depending on the characteristics monization of the different risk assessment models.
of the populations studied.34 The FRS, for example, has been The 3 most important features of a risk prediction model
shown to both overestimate and underestimate risk in different are the covariates included, the outcomes modeled, and the
populations.35 time horizon. Optimization of each of these features may help
further refine risk prediction techniques. As previously men-
Model Performance Characteristics tioned, most existing risk prediction models rely primarily on
Model calibration and discrimination are 2 features that can age, sex, cholesterol, blood pressure, hypertensive treatment
be used to assess the performance of risk prediction models. status, diabetes mellitus, and smoking status. These individual
Calibration, estimated by the Hosmer-Lemeshow statistic, rep- measurements do not account for variations in lifetime expo-
resents how well the predicted risk approximates the observed sure to risk factors. Because traditional cardiovascular risk
risk. Discrimination, measured by the c statistic, refers to how factors generally lead to atherosclerosis over decades, it is
1802CirculationMay 3, 2016

reasonable to hypothesize that the duration of exposure may that are independent of chronological age such as estimating
be important. This approach is commonly used for cigarette cardiovascular age or lifetime risk are appealing alternatives
smoking, which is recorded in pack-years of exposure, and because the primary prevention of ASCVD during the life
there is evidence to support a similar approach with hyperten- course, as opposed to during 10-year windows, is the ultimate
sion and dyslipidemia.3941 It is also notable that family history aim. Reflecting this concept, the Pooled Cohort equations pro-
of premature CHD is included in the QRISK2 model and the vide an estimated lifetime risk for individuals 20 to 59 years
modification of the FRS endorsed by the CCS but is not incor- of age, and the 2012 CCS guidelines endorse the use of heart
porated into the SCORE or Pooled Cohort equations models. age in clinical decision making. However, further research is
Because, as cited by the 2012 CCS guidelines, there are data required to determine how best to apply these assessments in
supporting a 2-fold increased risk in those with a family his- routine care and to develop an evidentiary basis for interven-
tory of premature CVD,21 it is intriguing that this variable did tions driven by such estimates.
not meet the criteria for inclusion in certain models. Perhaps,
it is related to how family history is defined or measured in Thresholds for Initiating Statin Therapy
the derivation cohorts. Although not included as a covariable Whether a result of improved accuracy or of an overestimation
in the Pooled Cohort equations model, the 2013 ACC/AHA of absolute risk, the Pooled Cohort equations partially explain
guideline included family history of premature CVD as an the increase in statin-eligible adults with the 2013 ACC/AHA
important factor that can be considered when a risk decision is guideline. However, the decision to lower the threshold at
uncertain. In addition to improving how established risk fac- which primary prevention statin treatment should be consid-
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tors are measured, discovery of new risk predictors (eg, using ered to an estimated 10-year absolute risk of ASCVD 7.5%
genomic data, biomarkers, and advanced imaging techniques) is another crucial factor. In fact, this is the lowest threshold
is an area of active investigation. used by the international guidelines reviewed here. High-
The optimal outcomes to include in a CVD risk prediction risk status was defined as an estimated 10-year risk of CHD
model remain uncertain. In particular, the inclusion of stroke >20% by the ATP III guidelines, fatal CVD 5% (equivalent
in the Pooled Cohort equations has been questioned. Although to 15% for nonfatal events) by the 2011 ESC/EAS guide-
CHD and myocardial infarction are almost exclusively caused lines, CVD 10% by the 2014 NICE guidelines, and 20%
by atherosclerotic disease, stroke is a heterogeneous disorder by the 2012 CCS guidelines. It should be noted that because
in which large-vessel atherosclerosis accounts for 40% of the outcomes included in the QRISK2 risk assessment tool
the disease burden.4244 Because blood cholesterol is directly endorsed by the NICE guidelines include softer diagnoses
related only to large-vessel atherosclerosis, using the same such as angina and transient ischemic attack, the 10% esti-
risk factors to predict CHD and stroke may be overly sim- mated risk by this calculation is likely to be qualitatively
plistic. In fact, low LDL-C has paradoxically been associated similar to the 7.5% absolute risk threshold of hard stroke and
with a higher risk of hemorrhagic stroke in some studies.45 myocardial infarction events used by the 2013 ACC/AHA
Furthermore, it is well described that the incidence of stroke in guideline. Furthermore, the decision to lower the threshold to
the United States varies widely by geographic region, giving 7.5% is supported by recent evidence demonstrating both the
rise to the term stroke belt to refer to a grouping of 11 south- benefits of statin therapy in primary prevention trials includ-
eastern US states with age-adjusted stroke mortality rates that ing those with relatively low risk and very small adverse event
are 10% higher than the national average.46 This area is not rates in meta-analyses of statin trials including 170000 par-
well represented in the 4 National Heart, Lung, and Blood ticipants.49 In a meta-analyses by the Cholesterol Treatment
Institute cohort studies used for the derivation of the Pooled Trialists Collaboration, statin treatment in people with a low
Cohort equations. Therefore, using these equations to estimate risk (<10%) of CVD resulted in an absolute reduction in major
the risk of stroke in the stroke belt will undoubtedly result in CVD events of 11 per 1000 over 5 years for each 39-mg/dL
underestimation. Lastly, stroke disproportionally affects the reduction in LDL-C, which greatly exceeded any observed
elderly, with 17% of all stroke patients >85 years of age, an hazard of statin therapy.50 A Cochrane review of statin efficacy
age group that is underrepresented in the discovery cohorts.47 in primary prevention similarly found that the number needed
Therefore, including stroke as an outcome might reduce model to treat to prevent an adverse CVD event was 167 for those
precision and could further contribute to increased weighting with an estimated 5-year risk of <5% and 67 for those with
of age in the risk prediction model. a 5-year risk of 5% to 10%.51 Moreover, using microsimula-
tion modeling, Pandya and colleagues52 recently demonstrated
Impact of Age on Absolute Risk Assessment that the 7.5% threshold is cost-effective, with an incremental
Indeed, the dramatic effect of age on estimated risk is an addi- cost-effectiveness ratio of $37000 per quality-adjusted life-
tional criticism of the Pooled Cohort equations, yet such age year gained.
effects are observed to some extent in all of the previously In addition to increasing the number of statin-eligible
mentioned risk prediction models. With the Pooled Cohort adults in the United States, another important consequence of
equations, many older adults may exceed the 7.5% estimated the lowering of the treatment threshold is a reduction in the
10-year ASCVD risk threshold even in the absence of smok- proportion of individuals considered to be at intermediate risk,
ing, diabetes mellitus, hypertension, or dyslipidemia.48 This which would decrease from 32% to 12% with full imple-
feature is partially a result of the commonly used 10-year time mentation of the ACC/AHA guideline.53 The most appropriate
window for risk prediction. The absolute event rate increases treatment for individuals at intermediate risk is, by definition,
with age, as will the predicted risk. Therefore, approaches 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- the continued use of cholesterol targets includes a number of
ommendations in this group. Significant attention has focused primary and secondary prevention statin trials demonstrat-
on developing and validating blood and imaging biomarkers ing improved outcomes with more intensive LDL-C lower-
to improve the precision of risk estimates for these individu- ing.49,50,5962 However, none of these trials used specific LDL-C
als. By lowering the treatment threshold, the 2013 ACC/AHA targets to trigger medication dose adjustments, so LDL-C
guideline is proposing that the recent evidence, reviewed targets are extrapolated from these trials. This is a highly
above, supports the use of statin therapy in most adults who controversial area in which randomized, controlled trial data
were previously in the intermediate-risk category and there- and everyday clinical practice appear to conflict. Innovative
fore that the group of individuals in whom there is equipoise investigative techniques are needed to evaluate the effects
concerning the most appropriate treatment has diminished. of treat-to-target strategies on patient outcomes, incorporat-
The international guidelines that we have reviewed endorse ing the short-term effects of lipid lowering and the long-term
basing treatment decisions on estimated absolute CVD risk. effects related to patient well-being and encouraging healthy
However, recent publications have suggested potential modifi- lifestyle behaviors.
cations to these methods. Navar-Boggan and colleagues54 have Two developments since the publication of the 2013 ACC/
recently demonstrated the potential benefit of using age- and AHA guideline may further complicate the target-agnostic
sex-specific 10-year risk thresholds to guide therapy, includ- approach. First is the publication of the results from the Improved
ing raising the treatment threshold for adults 66 to 75 years of Reduction of Outcomes: Vytorin Efficacy International Trial
age to 10% in women and 15% in men. Alternatively, Ridker (IMPROVE-IT), which demonstrated a 2% absolute risk reduc-
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and colleagues55 have proposed a hybrid algorithm that would tion of CVD events with ezetimibe added to statin therapy in
incorporate clinical trial data into the primary prevention algo- patients after myocardial infarction.10 Individuals receiving
rithm, although the superiority of this strategy is uncertain.56 the combination of simvastatin and ezetimibe had lower aver-
These strategies warrant additional investigation to determine age LDL-C levels (53.2 versus 69.9 mg/dL), suggesting that
whether they might be used to improve future cholesterol lower is better for LDL-C cholesterol, at least in the context
guidelines. of secondary prevention. The second development is the recent
approval by the US Food and Drug Administration of 2 drugs
Treatment Targets for from the new class of proprotein-convertase subtilisin/kexin
Lipid-Lowering Treatment type 9 inhibitors. While studies assessing the impact on hard
Another important modification introduced by the 2013 CVD outcomes are ongoing, these drugs appear to be safe and
ACC/AHA guideline was the removal of specific treatment effective in lowering LDL.63 The IMPROVE-IT trial was the
targets for lipid-lowering therapy. In explaining its rationale, first to demonstrate the benefit of adding a nonstatin medication
the guideline committee referred to the absence of clinical in patients already treated with statins for secondary preven-
trial data indicating what the precise targets should be, the tion. As the options for nonstatin LDL-Clowering medications
lack of proven benefit for 1 target versus another, the inability proliferate, future guideline committees will be tasked with
to account for adverse effects of striving to achieve a given evaluating whether a return to LDL-C treatment targets (at least
goal, and concern that target-based strategies may result in certain circumstances) might be warranted to guide the addi-
in undertreatment with statins or overtreatment with non- tion of these new pharmacological options in certain high-risk
statins to reach these goals.11 Additionally, there are small patients already treated with statins.64
but significant differences between estimating LDL-C con-
centrations with the Friedewald formula and direct measure- Primary Prevention Approaches for
ments.57 Thus, with a treat-to-target strategy, the same patient Those With Diabetes Mellitus or CKD
might have different recommendations depending on the Despite variations in the language used and details about the
LDL-C assay used. On the other hand, critics of this tar- suggested statin dose, the international guidelines generally
get-agnostic approach have argued that treatment goals are agree on the approach to primary prevention in those with dia-
valuable in clinical practice in that they serve to reinforce betes mellitus (Table2 provides details). The notable differ-
patients positive behaviors and lifestyle changes and provide ences pertain mostly to the treatment of patients <40 years of
patients and their providers with tangible goals and metrics.58 age, in whom there is scant evidence on the appropriateness of
Furthermore, removing treatment targets makes it difficult for statin treatment for the primary prevention of CVD.
patients to improve their risk profiles (by nonpharmacologi- Agreement among the guidelines is less uniform for the
cal means) sufficiently to no longer warrant pharmacother- treatment of individuals with CKD. The 2013 ACC/AHA
apy. Starting a preventive medication without the possibility guideline is alone among the international guidelines reviewed
of discontinuing the medication in the future may be a philo- in not considering the presence of CKD to confer high risk.
sophical challenge from a public health perspective because it The 2011 ESC/EAS and 2012 CCS guidelines characterize
essentially medicalizes a large proportion of the community patients with CKD as high to very high risk and recommend
while de-emphasizing the potential importance of lifestyle statin treatment to achieve the appropriate LDL-C targets.16,18
modifications. The 2014 NICE guidelines recommend starting atorvastatin
Although the most recent NICE guidelines similarly do 20 mg for all patients with CKD.17 The 2013 ACC/AHA, 2011
away with treatment targets, the latest ESC/EAS and CCS ESC/EAS, 2014 NICE, and 2012 CSS documents all agree
guidelines continue to endorse treat-to-target strategies.16,18 that there is insufficient evidence to support specific recom-
In the ESC/EAS and CCS guidelines, the justification for mendations for patients with end-stage renal disease receiving
1804CirculationMay 3, 2016

regular hemodialysis. Although the 2013 ACC/AHA guide- settings (beginning with a clinician-patient discussion) to a
line is unique among the international guidelines reviewed 10-year absolute ASCVD risk of 7.5%, and removing choles-
in not treating all individuals with CKD as high risk, using terol treatment targets. After reviewing several leading inter-
data from the REGARDS study, Colantonio and colleagues65 national guidelines, we observe a lack of consensus on the
demonstrated that only 8% of individuals with CKD who are optimal approach to risk assessment, treatment thresholds,
50 to 79 years of age would not qualify for consideration of or the use of cholesterol targets among these guidelines. As a
statin therapy on the basis of the 2013 ACC/AHA guideline. result, the recommendations for primary prevention lipid-low-
Therefore, whether this distinction between the 2013 ACC/ ering therapy for an individual vary according to which guide-
AHA and other guidelines actually affects individual-level line is followed, as illustrated by the clinical vignette. These
recommendations is uncertain. observations underscore the importance of further investiga-
tion aimed at refining risk prediction models and determining
Other Recent US Guidelines the optimal strategies for monitoring and adjusting medical
Since the publication of the 2013 ACC/AHA guideline, the therapy.
US Preventive Services Task Force (USPSTF)48 and National
Lipid Association (NLA)66 have released recommendations Sources of Funding
for CVD prevention. Agreement between the recommenda- Dr Nayor was supported by training grant T32-HL007604 from the
tions from the USPSTF draft statement (which focuses on National Institutes of Health and by the Clinical Skills Development
Core Training National Heart, Lung, and Blood Institute
primary prevention) and the 2013 ACC/AHA guideline is
Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

U10HL110337. Dr. Vasan was supported by the National Heart,


generally strong. The USPSTF recommendations support the Lung, and Blood Institutes Framingham Heart Study contracts
use of the Pooled Cohort equations for absolute risk assess- N01-HC-25195 and HHSN268201500001I.
ment and suggest matching the intensity of statin therapy to
absolute risk (as opposed to the treat-to-target approach of Disclosures
other guidelines). One notable difference, however, is that None.
the USPSTF recommendations require individuals to have a
10-year risk of ASCVD of 10% (as opposed to 7.5%) and References
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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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doi: 10.1161/CIRCULATIONAHA.116.021407
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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-
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
damente un tercio del total de las muertes son an atribuibles cm) de estatura y pesa 180 lb (81,6 kg); su ndice de masa
a enfermedad cardaca isqumica y accidente cerebrovascular.1 corporal es de 26,6 kg/m2; su tensin arterial es de 144/86
Estas condiciones tambin dan cuenta de una gran proporcin mmHg y su perfil lipdico en ayunas revela un colesterol s-
de discapacidad y costos en atencin de la salud globales.2,3 El rico total de 195 mg/dl, colesterol de la lipoprotena de baja
colesterol plasmtico elevado se encuentra entre los factores de densidad (LDL) de 125 mg/dl, colesterol de la lipoprotena de
riesgo cardiovascular modificables ms prevalentes, con trata- alta densidad (HDL) de 50 mg/dl, y triglicridos de 100 mg/dl
mientos mdicos probados para reducir tanto la incidencia de (para convertir de mg/dl a mmol/l, multiplicar LDL o HDL por
ECV como la mortalidad relacionada.4-10 Por lo tanto, las guas 0,0259 y multiplicar triglicridos por 0,0113).
de prctica clnica dirigidas al tratamiento del colesterol plasm-
tico tienen un impacto potencial tremendo sobre la salud de la Guas 2013 de American College of Cardiology/
poblacin y los costos de atencin de la salud relacionados. Las American Heart Association
guas de EE.UU. ms recientes para el tratamiento del colesterol
plasmtico11 contienen cambios importantes de la versin pre-
Metodologa
Las guas 2013 de American College of Cardiology/American
via.12,13 En esta revisin, nos proponemos resumir las recomen-
Heart Association Guideline on the Treatment of Blood
daciones de las guas de colesterol de EE.UU. ms recientes,
Cholesterol to Reduce Atherosclerotic Cardiovascular Risk
destacando los cambios especficos de la versin previa, y en
in Adults11 (gua ACC/AHA 2013) fue encargada de reflejar
paralelo compararla con otras guas internacionales destacadas.
una nueva evidencia ya que las previas guas Adult Treatment
Panel III (ATP III) fueron actualizadas por ltima vez en
Guas para el tratamiento del colesterol plasmtico 2004.12,13 Mientras que las guas de colesterol previas se en-
Vieta clnica focaron en la prevencin de la enfermedad cardaca coronaria
Para mostrar las diferencias entre las diversas guas, nos referi- (EC), las guas ACC/AHA 2013 ampli el foco a ECV ate-
mos a un paciente representativo (Figura): Considerar un hom- roesclertica (ECV AS), incluyendo EC, accidente cerebro-
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 DOI: 10.1161/CIRCULATIONAHA.116.021407
41
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 and Blood Institute -4 estudios de cohorte patrocinados- el
ACC/AHA 2013 utiliz un nuevo abordaje para evaluar la estudio Atherosclerosis Risk in Communities (ARIC), el estu-
evidencia disponible, poniendo el foco en los estudios contro- dio Cardiovascular Health Study (CHS), el estudio Coronary
lados aleatorizados y revisiones sistemticas y metaanlisis de Artery Risk Development in Young Adults (CARDIA), y el
estudios controlados aleatorizados. Adems, las nuevas guas Framingham Heart Study (FHS; incluyendo cohortes origina-
difirieron de las previas en su mbito de aplicacin. Mientras les y de la descendencia) - con resultados clnicos adjudicados,
que las guas ATP III incluan una revisin tpica amplia y incluyendo infarto de miocardio, muerte por EC y accidente
recomendaciones para evaluacin de laboratorio, diagnstico cerebrovascular fatal y no fatal.14 Los factores de riesgo que re-
clnico, intervenciones en el estilo de vida y tratamiento far- nen los criterios de inclusin en el modelo multivariable fue-
macolgico, las guas ACC/AHA 2013 se enfocaron en res- ron edad, sexo, colesterol total, HDL, tensin arterial sistlica,
ponder 3 cuestiones crticas: (1) Cul es la evidencia de los estado del tratamiento antihipertensivo, diabetes mellitus y es-
objetivos de LDL y no-HDL en la prevencin secundaria de tado del hbito de fumar actual. De estas variables, slo la dia-
ECV AS? (2) Cul es la evidencia de los objetivos de LDL betes mellitus no fue incluida en el FRS modificado aprobado
y no-HDL en la prevencin primaria de ECV AS? (3) Cul por las guas ATP III. Se construyeron diferentes modelos mul-
es la eficacia y seguridad de los frmacos modificadores de tivariables para individuos blancos y negros, y se recomend
lpidos en la prevencin primaria y secundaria de ECV AS?11 precaucin cuando estas ecuaciones se aplicaron a otras razas y
Un profesional independiente contratado seleccion los estu- adultos fuera de los rangos de edad de 40 a 79 aos.
dios relevantes para ser revisados para cada cuestin crtica de
acuerdo con los criterios preespecificados. Esta metodologa Recomendaciones de tratamiento
fue diseada para reducir el sesgo y asegurar que los estudios Las guas ACC/AHA 2013 recomendaron el tratamiento con
de baja calidad no fueran considerados cuando se formulasen inhibidores de la 3-hidroxi-3-metilglutaril-coenzima A reduc-
las recomendaciones. tasa (estatinas) para 4 categoras de individuos: (1) preven-
cin secundaria para aquellos con ECV AS establecida, (2)
Modelo de evaluacin del riesgo prevencin primaria de ECV AS para aquellos con LDL 190
Con las guas ACC/AHA 2013 se introdujo una nueva herra- mg/dl, (3) prevencin primaria de ECV AS para individuos con
mienta para la evaluacin del riesgo global.11 Las guas pre- diabetes mellitus y LDL de 70 a 189 mg/dl, y (4) prevencin
vias recomendaban utilizar un Framingham Risk Score (FRS) primaria de ECV AS para aquellos sin diabetes mellitus, con
modificado para estimar el riesgo a 10 aos de infarto de mio- LDL de 70 a 189 mg/dl, pero con un riesgo absoluto a 10 aos
cardio o muerte por EC. Las crticas a este modelo incluyeron estimado de 7,5% evaluado por las ecuaciones de la Cohorte
la ausencia de accidente cerebrovascular como resultado de Agrupada. Para este cuarto grupo en especial, los autores de las
una falta de diversidad racial, tnica y geogrfica en la pobla- guas enfatizan la importancia de tomar las decisiones de for-
cin de derivacin. En respuesta, las ecuaciones de la Cohorte ma compartida con base en una discusin detallada del riesgo
Agrupada se obtuvieron con datos de National Heart, Lung 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 43

miento con estatinas.15 La discusin mdico-paciente debera timado de EC del 10%. Por consiguiente, su objetivo de LDL
incluir una evaluacin del beneficio potencial, posibles efectos sera <130 mg/dl, y dado su actual LDL de 125 mg/dl, l no
adversos e interacciones medicamentosas, cambios en el estilo recibira tratamiento con estatinas.
de vida, manejo de otros factores de riesgo y por supuesto las Notablemente, fue utilizado un hombre blanco para nuestra
preferencias del paciente. De manera adicional, otros factores vieta clnica representativa. La diferencia en el riesgo esti-
que pueden afectar la reclasificacin del riesgo neto podran mado entre las ecuaciones de la Cohorte Agrupada y el FRS
utilizarse para informar mejor la decisin de tratamiento; stos sera ms pronunciada si una mujer negra, por ejemplo, tuvie-
incluyen LDL 160 mg/dl o evidencia de dislipidemia genti- se el mismo perfil de factor de riesgo. Con las ecuaciones de
ca, riesgo de vida elevado, historia familiar de ECV prematura, la Cohorte Agrupada, ella tendra un riesgo de ECV AS a 10
niveles plasmticos de protena C-reactiva de alta sensibilidad aos de 7,4%, que es considerablemente ms alto que el 2% de
2,0 mg/l, ndice tobillo braquial <0,9, o puntaje de calcio de riesgo de EC a 10 aos estimado por el FRS.
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 Guas 2011 de European Society of Cardiology/
riesgo (<5% de riesgo absoluto a 10 aos) podran tambin European Atherosclerosis Society
considerarse para el tratamiento con estatinas sobre la base de Metodologa
las preferencias del paciente o del beneficio percibido basado Las Guidelines for the Management of Dyslipidaemias16 de
en factores adicionales como aquellos listados ms arriba. la European Society of Cardiology/European Atherosclerosis
En lugar de establecer objetivos especficos de LDL, las Society (guas 2011 ESC/EAS) son un documento amplio di-
guas ACC/AHA 2013 en esencia sugirieron una dosis fija (o rigido a la evaluacin del riesgo cardiovascular, evaluacin de
intensidad) de estatinas para cada categora de riesgo, con la laboratorio, modificaciones de estilo de vida, tratamiento far-
intencin de una reduccin del LDL del 30% al 49% y 50% macolgico y el abordaje de cuadros clnicos especficos como
para estatinas de moderada y alta intensidad respectivamente. las dislipidemias familiares. La fuerza de tareas de ESC/EAS
Los autores tambin sugirieron que las medicaciones no esta- bas sus hallazgos en una amplia revisin de la literatura en
tinas podan considerarse para aquellos en alto riesgo (preven- la que la mayor confianza fue colocada en los resultados de
cin secundaria, diabetes mellitus, LDL 190 mg/dl) si tienen estudios controlados aleatorizados, pero que fue inclusiva de
intolerancia a la dosis recomendada de estatinas o tienen una todos los diseos de estudio.
respuesta inadecuada a las estatinas. Aunque no se aprobaron
objetivos de LDL especficos, las guas ACC/AHA 2013 reco- Modelo de evaluacin de riesgo
mendaron el monitoreo de los niveles de lpidos plasmticos De manera similar a las guas ACC/AHA 2013, las guas 2011
para asegurar adherencia, respuesta teraputica y seguridad. ESC/EAS apoyan el uso de rutina de la evaluacin del riesgo
En comparacin, las guas ATP III recomendaron una estra- cardiovascular global para todos los adultos sin ECV estable-
tegia para tratar segn el objetivo con la finalidad de LDL es- cida pero aprobaron el uso de la herramienta de evaluacin
pecficos para cada grupo de riesgo. Para la prevencin prima- de riesgo Systemic Coronary Risk Evaluation (SCORE). La
ria, la meta de LDL se puso a <100 mg/ml para los individuos herramienta SCORE, derivada de los datos agregados de estu-
de alto riesgo (riesgo de EC a 10 aos >20%), <130 mg/dl para dios de cohorte con participantes de 12 pases europeos, est
aquellos en riesgo intermedio (riesgo de EC a 10 aos, 10%- diseada para estimar el riesgo a 10 aos de un evento ECV fa-
20%), y <160 mg/dl para los individuos de bajo riesgo (riesgo tal.19 La decisin de incluir solamente eventos de resultado fa-
de EC a 10 aos <10%). La meta de LDL para prevencin tal se bas en la evaluacin de que los eventos fatales son ms
secundaria o prevencin primaria de ECV en aquellos con dia- fcilmente calibrados en diferentes poblaciones y son menos
betes mellitus fue <100 mg/dl, con la opcin de apuntar a <70 probables que los eventos no fatales de ser afectados por varia-
mg/dl para aquellos con el riesgo ms alto de ECV.12,13 ciones geogrficas locales en el diagnstico y tratamiento.19 La
En resumen, las diferencias ms importantes entre las guas tasa de eventos de ECV total (incluidos eventos no fatales) ha
ACC/AHA 2013 y las guas ATP III son la introduccin de mostrado ser 3 veces ms alta que la tasa de eventos ECV fa-
las ecuaciones de la Cohorte Agrupada, la eliminacin de los tales.16 Las variables incluidas en el modelo de riesgo SCORE
objetivos de tratamiento de LDL y la disminucin del umbral incluyen edad, sexo, tensin arterial sistlica, colesterol total
al cual las estatinas deberan considerarse para un riesgo ab- y estado del hbito de fumar, y se utilizan modelos separados
soluto a 10 aos estimado de 7,5%. Las diferencias entre estos para pases europeos de alto y bajo riesgo.
2 documentos se resumen en la Tabla 1. Para proveer un con-
texto adicional para las guas ACC/AHA 2013, a continuacin Recomendaciones de tratamiento
compararemos sus recomendaciones con aqullas de otras De acuerdo con las guas 2011 ESC/EAS, los pacientes se con-
guas internacionales destacadas, como se seala en la Tabla 2. sideran de muy alto riesgo por ECV documentada, diabetes
mellitus tipo 2, diabetes mellitus tipo 1 con dao de rgano
Vieta clnica blanco, enfermedad renal crnica moderada a severa (ERC),
Con las ecuaciones de la Cohorte Agrupada, el paciente de o riesgo absoluto a 10 aos estimado de ECV fatal 10%. Los
nuestra vieta clnica tendra un riesgo estimado de ECV AS individuos de alto riesgo son aquellos con un riesgo a 10 aos
absoluto a 10 aos del 10,3%, y podra considerarse un trata- de ECV fatal del 5% al 9,9% o elevaciones marcadas de facto-
miento con estatinas de moderada a alta densidad despus de res de riesgo como dislipidemia familiar o hipertensin severa.
una discusin mdico-paciente de la potencial reduccin del El riesgo moderado se define como riesgo a 10 aos de ECV
riesgo, efectos adversos, interacciones medicamentosas y pre- fatal de 1% a 4,9%, y bajo riesgo se define como un riesgo a
ferencias del paciente. Con el FRS modificado aprobado por 10 aos de evento ECV fatal estimado <1%. Extrapolando de
las guas ATP III, por otra parte, l sera considerado en riesgo estudios clnicos, la fuerza de tareas recomend metas de LDL
intermedio sobre la base de un riesgo absoluto a 10 aos es- 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 Guas 2014 de National Institute for Health and
(3,0 mmol/l) para riesgo moderado, y <190 mg/dl (4,9 mmol/l) Care Excellence
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 Metodologa
evaluacin de riesgo, el riesgo estimado a 10 aos se consider Las guas para la modificacin de lpidos del National Institute
suficiente para justificar tratamiento mdico, y la aprobacin for Health and Care Excellence (NICE) en Inglaterra fueron
continuada de objetivos de LDL para guiar el tratamiento. actualizadas por ltima vez en 2014.17 Las guas NICE son de
alcance similar a las guas ACC/AHA 2013, con recomenda-
Vieta clnica ciones para la prevencin primaria y secundaria de ECV. De
De acuerdo con la herramienta de evaluacin del riesgo las guas internacionales revisadas, las guas NICE son nota-
SCORE, nuestro paciente tiene un riesgo estimado a 10 aos bles por la especificidad de las recomendaciones farmacolgi-
de mortalidad por ECV de 5% si vive en un pas europeo de cas provistas y por el grado en el que se utilizan los anlisis
alto riesgo y sera considerado de alto riesgo. Si l vive en costo-eficacia para justificar las recomendaciones.
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- Modelo de evaluacin de riesgo
siderado de riesgo moderado. Independientemente de su pas Las guas NICE apoyan el uso de la herramienta de evaluacin
de residencia, el tratamiento con estatinas sera recomendado, de riesgo QRISK2 para la evaluacin del riesgo cardiovascular
dado los objetivos de LDL de <100 mg/dl para alto riesgo y global en todos los adultos <84 aos de edad libres de ECV.
<115 mg/dl para individuos de riesgo moderado. 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- multivariable QRISK2 incluye factores de riesgo adicionales
lar, o accidente isqumico transitorio; est especficamente tales como etnicidad, historia familiar de EC prematura, de-
calibrado para la poblacin britnica y se actualiza anualmen- privacin socioeconmica, ndice de masa corporal, artritis
te. Comparado con las ecuaciones de la Cohorte Agrupada y reumatoidea, ERC y fibrilacin auricular (adems de edad,
la herramienta de evaluacin del riesgo SCORE, el modelo sexo, tensin arterial sistlica, colesterol total, HDL, estado
46 Circulation Octubre 2016

del tratamiento de la hipertensin, diabetes mellitus y estado mg/dl. Por lo tanto, no se le debera recomendar recibir tra-
del hbito de fumar, que estn incluidos en las ecuaciones de tamiento con estatinas.
la Cohorte Agrupada).20
Comparacin de las guas internacionales
Recomendaciones de tratamiento Las guas ACC/AHA 2013 difieren sustancialmente de su ver-
De manera semejante a las guas ACC/AHA 2013, las guas sin previa, las guas ATP III, y de otras guas internaciona-
NICE 2014 no aprueban una estrategia de tratar segn un ob- les destacadas. Los efectos de estos cambios se ilustraron con
jetivo. En cambio, el tratamiento con estatinas se recomienda nuestra vieta clnica representativa, en la que las recomenda-
para la prevencin primaria en individuos con diabetes melli- ciones para iniciar tratamiento con estatinas para un hombre de
tus tipo 2 o en aquellos sin diabetes mellitus pero con un riesgo 60 aos de edad con factores de riesgo cardiometablico mo-
de ECV absoluto a 10 aos estimado 10%. El tratamiento destos difirieron de acuerdo con las guas seguidas (Figura).
con estatinas tambin se recomienda para pacientes con dia- Las guas internacionales destacadas incluidas en esta revisin
betes mellitus tipo 1 que tienen >40 aos de edad con una du- difieren en 3 reas clave: el modelo de evaluacin de riesgo
racin de la enfermedad >10 aos o con evidencia de dao sugerido (factores de riesgo componentes y resultado evalua-
de rgano blanco. Se recomienda atorvastatina 20 mg por da do), el umbral de riesgo considerado suficiente para justificar
para prevencin primaria, y atorvastatina 80 mg por da para la iniciacin de tratamiento mdico, y la decisin de si usar
prevencin secundaria. En los pacientes con ERC, se sugiere una estrategia para tratar segn el objetivo.
atorvastatina 20 mg para prevencin primaria y secundaria.

Vieta clnica Impacto previsto de los cambios propuestos por


El paciente de nuestra vieta clnica tiene un riesgo de ECV las guas ACC/AHA 2013
estimado a 10 aos de 10,4% con el modelo QRISK2, y reu- La dislipidemia y los factores de riesgo cardiometablico son
nira as los criterios para tratamiento con estatinas como pre- altamente prevalentes en la poblacin; por lo tanto los cam-
vencin primaria. bios en las guas de tratamiento del colesterol afectarn las re-
comendaciones de tratamiento para mucha gente. Utilizando
Guas 2012 de Canadian Cardiovascular Society datos de las National Health and Nutrition Examination
Surveys (NHANES), Pencina y colegas demostraron que 13
Metodologa y modelo de evaluacin del riesgo millones de adultos americanos seran elegibles para iniciar
Las guas de la Canadian Cardiovascular Society (CCS) para tratamiento con estatinas con la implementacin plena de
el diagnstico y tratamiento de la dislipidemia para la preven- las guas ACC/AHA 2013.23 El aumento en la elegibilidad de
cin de ECV en adultos fue actualizada por ltima vez en 2012 las estatinas fue principalmente atribuible a una proporcin
(guas CCS 2012).18 Las guas CCS 2012 recomiendan utilizar ms alta de individuos de 60 a 75 aos de edad que renen
el FRS para eventos de la ECV total para estimar el riesgo criterios para tratamiento, que creci de 47,8% con las guas
absoluto a 10 aos. Estas guas tambin sugieren duplicar el ATP III a 73,3% con las guas ACC/AHA 2013. El verdade-
riesgo absoluto estimado para individuos con historia familiar ro impacto de las guas ACC/AHA 2013 probablemente est
de ECV prematura sobre la base de la evidencia de un aumento sobreestimado por estos clculos, que asumen que todos los
de 2 veces el riesgo de ECV para los participantes de FHS con individuos en un grupo con beneficio de las estatinas seran
una historia familiar de ECV prematura.21 Los autores de las tratados con estatinas y por lo tanto no consider el efecto de
guas CCS 2012 aconsejan considerar la edad cardiovascu- una discusin mdico-paciente (especficamente enfatizado
lar adems del riesgo absoluto estimado a 10 aos cuando por las nuevas guas) de los riesgos y beneficios de comen-
se discute el tratamiento de disminucin de lpidos con los zar con estatinas. No obstante, se predice que las guas ACC/
pacientes. Edad cardiovascular y edad del corazn pue- AHA 2013 darn como resultado un nmero mayor de indivi-
den ser conceptos ms fciles de entender por los pacientes duos elegibles para estatinas en los Estados Unidos.
y pueden facilitar de este modo el compartir la decisin entre El impacto general de una proporcin mayor de poblacin
paciente y mdico.22 que recibe tratamiento con estatinas es incierto. Aunque el so-
bretratamiento es una preocupacin,24 varios estudios recientes
Recomendaciones de tratamiento han sugerido que las guas ACC/AHA 2013 se alinean ms es-
Las guas CCS 2012 aprueban una estrategia de tratar segn trechamente que las guas ATP III con la carga ateroesclertica
el objetivo con metas de LDL de <75 mg/dl (2,0 mmol/l) para coronaria, evaluada con el puntaje de calcio arterial coronario
los pacientes de alto riesgo (riesgo absoluto a 10 aos 20%, y la angiografa con tomografa computada.25,26 Las caracters-
ERC, o hipertensin de alto riesgo), <130 mg/dl (3,5 mmol/l) ticas principalmente responsables de las diferencias en la asig-
para los individuos de riesgo intermedio (riesgo absoluto a 10 nacin de estatinas cuando se comparan las guas ACC/AHA
aos, 10%-19%), y <190 mg/dl (5 mmol/l) para aquellos de 2013 con las guas ATP III son los modelos de evaluacin del
bajo riesgo (riesgo absoluto a 10 aos <10%). Un objetivo de riesgo utilizados y el aumento potencial en la asignacin de
LDL de <75 mg/dl se recomienda tambin para aquellos con estatinas a la prevencin primaria de bajo riesgo.
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. Estimacin del riesgo absoluto:
una crtica comparativa
Vieta clnica Las ecuaciones de la Cohorte Agrupada se introdujeron junto
El paciente de nuestra vieta clnica tiene un riesgo esti- a las guas ACC/AHA 2013 con las metas de ampliacin y di-
mado de 10 aos de ECV total de 16,6% de acuerdo con el versidad tnica y geogrfica y la incorporacin del accidente
FRS y debera caracterizarse como de riesgo intermedio. El cerebrovascular como un resultado en el modelo de predic-
objetivo de LDL para el grupo de riesgo intermedio es <130 cin del riesgo.14 Desde su publicacin, varias caractersticas
Nayor y Vasan Una comparacin de las guas para el tratamiento del colesterol 47

de las ecuaciones de la Cohorte Agrupada han sido critica- que la calibracin fue similarmente mediocre en los tres mo-
das, incluyendo la sobreestimacin potencial del riesgo ab- delos, todos los cuales sobreestimaron significativamente el
soluto, la dependencia de la edad cronolgica y la derivacin riesgo del primer evento de ECV.24 Adems, la discrimina-
en cohortes ms viejas con menor rendimiento en cohortes cin fue modesta (ms alta con la herramienta SCORE) entre
ms contemporneas. los tres modelos (la estadstica c en el rango de 0,67-0,77).24
De manera semejante, los investigadores de la cohorte MESA
Estimacin del riesgo absoluto evaluaron el desempeo de 3 diferentes ecuaciones del FRS,
La sobreestimacin del riesgo fue informada primero en las el Reynolds Risk Score y la Cohorte Agrupada.31 Ellos en-
guas ACC/AHA 2013 sobre la evaluacin del riesgo cardiovas- contraron una calibracin modesta para los 5 puntajes, con
cular, durante la validacin externa con datos de las ms con- discriminacin superior cuando se utiliz el Reynolds Risk
temporneas cohortes Multi-Ethnic Study of Atherosclerosis Score. A pesar de las diferencias demostradas en los estudios
(MESA) y Reasons for Geographic and Racial Differences de ms arriba, hay un pequeo consenso sobre el modelo de
in Stroke (REGARDS), y con datos actualizados de ARIC y previsin de riesgo ptimo.
FHS.14 Se han propuesto varias explicaciones para estos ha-
llazgos. Ante todo, se requiri un seguimiento de por lo menos Eleccin de variables y optimizacin de modelos
12 aos de las cohortes de derivacin para predecir con preci- Los diferentes modelos de previsin de riesgo aprobados por
sin el riesgo a 10 aos. Por lo tanto, las tendencias duraderas las guas de colesterol internacionales difieren poco en trmi-
en el uso de estatinas, los procedimientos de revascularizacin nos de los factores de riesgo incluidos como pronstico, sien-
o el tratamiento de otros factores de riesgo como la hiper- do el modelo QRISK2 notable por la incorporacin de varia-
tensin y la diabetes mellitus pueden dar cuenta de las tasas bles adicionales. Podra considerarse en el futuro la evaluacin
ms bajas de ECV observadas en cohortes ms contempor- del inters, oportunidad y factibilidad de establecer un marco
neas.27-29 La verificacin insuficiente de eventos clnicamente ms unificado para la estimacin global del riesgo cardiovas-
relevantes en la validacin de cohortes puede tambin explicar cular, quizs mediante el desarrollo de un modelo de previsin
la aparente sobreestimacin. De hecho, cuando los investiga- de riesgo ECV internacional. Cuando los datos de las cohor-
dores utilizaron datos de reclamos de Medicare para mejorar tes internacionales estn combinados, puede optimizarse la
la verificacin de resultados para el estudio REGARDS, de- diversidad geogrfica, racial y tnica. La factibilidad de este
mostraron mejora de la performance de las ecuaciones de la abordaje y la capacidad para calibrar el puntaje de riesgo para
Cohorte Agrupada.28 Sin embargo, las preocupaciones acerca diferentes pases fue demostrada recientemente.37 Por supues-
de las ecuaciones de la Cohorte Agrupada se mantienen. La to, hay varios obstculos importantes para la bsqueda global
sobreestimacin ha sido repetidamente demostrada en varias de este abordaje. Entre stos es primaria la falta de datos de
cohortes modernas,24,30,31 y en por lo menos el Womens Health ciertos grupos geogrficos y tnicos. Por ejemplo, los as lla-
Study, la sobreestimacin no fue explicada por diferencias en mados pases BRIC, Brasil, Rusia, India y China, representan
el uso de estatinas, revascularizaciones o verificacin insu- 40% de la poblacin del mundo, pero los datos sobre evalua-
ficiente.27 A pesar de estos hallazgos, debera notarse que el cin del riesgo cardiovascular en estos pases son limitados.38
Womens Health Study fue un estudio de prevencin primaria Adems, es incierto el grado en que la evaluacin del riesgo
compuesto por voluntarias del estudio clnico.32 El riesgo ms individual est afectada por caractersticas locales que no son
bajo observado en este estudio puede por lo tanto ser atribuible fciles de evaluar o integrar en los modelos de prediccin de
parcialmente al efecto de voluntarias sanas.33 riesgo. Estos pueden incluir factores como el medio ambiente
Aunque la investigacin adicional del desempeo de las local, dieta, clima, polucin atmosfrica, medio edilicio, fac-
ecuaciones de la Cohorte Agrupada puede justificarse, vale tores culturales, disponibilidad de atencin de salud y ante-
la pena considerar si otros modelos de previsin de riesgo cedentes genticos. Con el paciente representativo de nuestra
existentes se desempean mejor. Esta cuestin est subrayada vieta clnica, observamos diferencias importantes en el riesgo
por la observacin de que cada una de las guas internaciona- estimado utilizando cada uno de los 5 modelos de evaluacin
les destacadas aprueba un modelo de evaluacin del riesgo de riesgo. Aunque estas diferencias pueden ser parcialmente
diferente. Lamentablemente, las comparaciones sistemticas explicadas por caractersticas especficas del modelo, los fac-
entre los modelos de previsin de riesgo son raras, y los re- tores locales nicos pueden contribuir adicionalmente a varia-
sultados son frecuentemente conflictivos, dependiendo de las ciones en la ponderacin de variables que podran complicar
caractersticas de las poblaciones estudiadas.34 El FRS, por la comparacin directa o la armonizacin de los distintos mo-
ejemplo, ha mostrado sobreestimar y subestimar el riesgo en delos de evaluacin de riesgo.
diferentes poblaciones.35 Las tres caractersticas ms importantes de un modelo de
previsin de riesgo son las covariables incluidas, los resulta-
Caractersticas del desempeo del modelo dos modelados y el horizonte de tiempo. La optimizacin de
La calibracin y la discriminacin del modelo son 2 caracte- cada una de estas caractersticas puede ayudar a refinar ms
rsticas que pueden usarse para evaluar el desempeo de los las tcnicas de prediccin de riesgo. Como fue previamente
modelos de previsin de riesgo. La calibracin, estimada por mencionado, la mayora de los modelos de prediccin de ries-
la estadstica de Hosmer-Lemeshow, representa cun bien el go existentes descansan ante todo en la edad, sexo, colesterol,
riesgo predicho se aproxima al riesgo observado. La discri- tensin arterial, estado del tratamiento antihipertensivo, dia-
minacin, medida por la estadstica c, se refiere a cun bien betes mellitus y estado del hbito de fumar. Estas mediciones
el modelo distingue a aquellos que desarrollan la enferme- individuales no dan cuenta de las variaciones de la exposicin
dad de aquellos que no lo hacen.36 Con datos del Rotterdam de toda la vida a los factores de riesgo. Puesto que los factores
Study, los investigadores compararon el desempeo de las de riesgo cardiovascular tradicionales llevan a la ateroescle-
ecuaciones de la Cohorte Agrupada, el FRS modificado y la rosis a travs de dcadas, es razonable pensar que la duracin
herramienta de evaluacin de riesgo SCORE y determinaron de la exposicin debe ser importante. Este abordaje es co-
48 Circulation Octubre 2016

mnmente utilizado para el hbito de fumar cigarrillos, que se Agrupada, muchos adultos mayores pueden exceder el 7,5%
registran como paquetes-aos de exposicin y hay evidencia del umbral de riesgo estimado de ECV AS a 10 aos incluso
para apoyar un abordaje similar con la hipertensin y la disli- en ausencia de hbito de fumar, diabetes mellitus, hiperten-
pidemia.39-41 Es tambin notable que la historia familiar de EC sin o dislipidemia.48 Esta caracterstica es parcialmente un
prematura se incluye en el modelo QRISK2 y la modificacin resultado de la comnmente usada ventana de tiempo de 10
del FRS aprobado por la CCS, pero no est incorporada en aos para prediccin del riesgo. La tasa absoluta de eventos
los modelos de ecuaciones SCORE ni la Cohorte Agrupada. aumenta con la edad, como lo har el riesgo predicho. Por
Ya que, como est citado por las guas CCS 2012, hay datos lo tanto, los abordajes que son independientes de la edad
que apoyan un riesgo aumentado 2 veces en aquellos con un cronolgica tales como estimar la edad cardiovascular o el
historia familiar de ECV prematura,21 es interesante que esta riesgo de vida son alternativas atractivas porque la preven-
variable no reuni los criterios para inclusin en ciertos mo- cin primaria de la ECV AS durante el curso de la vida, como
delos. Quizs est relacionado con cmo se define la historia opuesta a la ventana de 10 aos de duracin, es el objetivo l-
familiar o se mide en las cohortes de derivacin. Aunque no timo. Reflejando este concepto, las ecuaciones de la Cohorte
est incluida como una covariable en el modelo de las ecua- Agrupada proveen un riesgo estimado de vida para individuos
ciones de la Cohorte Agrupada, las guas ACC/AHA 2013 in- de 20 a 59 aos de edad, y las guas CCS 2012 aprueban el
cluyeron la historia familiar de ECV prematura como un fac- uso de edad del corazn en la toma de decisiones clnicas. Sin
tor importante que puede considerarse cuando una decisin embargo, se requiere investigacin adicional para determinar
de riesgo es incierta. Adems, para mejorar cmo se miden cmo aplicar mejor estas evaluaciones en la atencin de ruti-
factores de riesgo establecidos, el descubrimiento de factores na y desarrollar una base probatoria para intervenciones im-
predictivos de riesgo nuevos (p. ej., utilizando datos genmi- pulsadas por tales estimaciones.
cos, biomarcadores y tcnicas de imgenes avanzadas) es un
rea de activa investigacin.
Los resultados ptimos para incluir en un modelo de previ- Umbrales para la iniciacin de tratamiento
sin de riesgo de ECV siguen siendo inciertos. En particular, con estatinas
la inclusin del accidente cerebrovascular en las ecuaciones Ya sea un resultado de mejora de la precisin o una sobre-
de la Cohorte Agrupada ha sido cuestionada. Aunque la EC estimacin del riesgo absoluto, las ecuaciones de la Cohorte
y el infarto de miocardio son casi exclusivamente causados Agrupada explican parcialmente el aumento de adultos ele-
por la enfermedad ateroesclertica, el accidente cerebrovascu- gibles para estatinas con las guas ACC/AHA 2013. Sin em-
lar es un trastorno heterogneo en el que la ateroesclerosis de bargo, otro factor crucial es la decisin de bajar el umbral al
los grandes vasos da cuenta de 40% de la carga de enferme- cual debera considerarse el tratamiento con estatinas de pre-
dad.42-44 Puesto que el colesterol plasmtico est directamente vencin primaria para un riesgo absoluto a 10 aos estimado
relacionado slo con la ateroesclerosis de los grandes vasos, de ECV AS 7,5%. De hecho, ste es el umbral ms bajo uti-
utilizar los mismos factores de riesgo para predecir la EC y el lizado por las guas internacionales revisadas aqu. El estado
accidente cerebrovascular puede ser demasiado simplista. De de alto riesgo fue definido como un riesgo a 10 aos estimado
hecho, el LDL ha sido paradjicamente asociado con un riesgo de EC >20% por las guas ATP III, ECV fatal 5% por cien-
ms alto de accidente cerebrovascular hemorrgico en algunos to (equivalente a 15% para eventos no fatales) por las guas
estudios.45 Adems, est bien descripto que la incidencia de ESC/EAS 2011, ECV 10% por las guas NICE, y 20% por
accidente cerebrovascular en los Estados Unidos vara amplia- las guas CCS 2012. Debera notarse que puesto que los re-
mente por regin geogrfica, dando lugar al trmino cinturn sultados incluidos en la herramienta de evaluacin de riesgo
de accidente cerebrovascular para referirse a la agrupacin de QRISK2 aprobadas por las guas NICE incluyen diagnsticos
11 estados del sudeste de EE.UU. con tasas de mortalidad por ms suaves como angor o accidente isqumico transitorio, el
accidente cerebrovascular ajustada por edad que son 10% ms riesgo estimado de 10% por este clculo es probable que sea
altas que el promedio nacional.46 Esta rea no est bien repre- cualitativamente similar al 7,5% de umbral de riesgo absoluto
sentada en los 4 estudios de cohorte del National Heart, Lung, de eventos de accidente cerebrovascular e infarto de miocar-
and Blood Institute utilizados para la derivacin de la Cohorte dio graves utilizado por las guas ACC/AHA 2013. Adems, la
Agrupada. Por lo tanto, utilizar estas ecuaciones para estimar decisin de bajar el umbral al 7,5% es apoyada por evidencia
el riesgo de accidente cerebrovascular en el cinturn de acci- reciente que demuestra que los beneficios del tratamiento con
dente cerebrovascular puede indudablemente resultar en una estatinas en estudios de prevencin primaria incluyen aque-
subestimacin. Por ltimo, el accidente cerebrovascular afecta llos con relativamente bajo riesgo y muy pequeas tasas de
de manera desproporcionada a la vejez, con 17% de todos los efectos adversos en los metaanlisis de estudios de estatinas
pacientes con accidente cerebrovascular >85 aos de edad, un que incluyen 170.000 participantes.49 En un metaanlisis de la
grupo de edad que est infrarrepresentado en las cohortes de Cholesterol Treatment Trialists Collaboration, el tratamiento
descubrimiento.47 Por lo tanto, incluir el accidente cerebrovas- con estatinas en gente con bajo riesgo (<10%) de ECV dio
cular como un resultado puede reducir la precisin del modelo como resultado una reduccin absoluta de eventos de ECV
y podra contribuir adicionalmente al aumento de la pondera- mayores del 11 por 1000 durante cinco aos por cada 39 mg/dl
cin de la edad en el modelo de prediccin de riesgo. de reduccin de LDL, lo cual excedi grandemente cualquier
riesgo observado de tratamiento con estatinas.50 Una revisin
Impacto de la edad en la evaluacin del riesgo absoluto Cochrane de la eficacia de las estatinas en la prevencin pri-
En efecto, el dramtico efecto de la edad sobre el riesgo esti- maria de manera similar encontr que el nmero necesario a
mado es una crtica adicional a las ecuaciones de la Cohorte tratar para prevenir un evento de ECV adverso fue de 167 para
Agrupada, sin embargo tales efectos de la edad se observan aquellos con un riesgo a 5 aos de <5% y de 67 para aquellos
en cierta medida en todos los modelos de previsin de riesgo con un riesgo a 5 aos estimado de 5% a 10%.51 Por otra parte,
mencionados previamente. Con las ecuaciones de la Cohorte utilizando modelado con microsimulacin, Pandya y colegas52
Nayor y Vasan Una comparacin de las guas para el tratamiento del colesterol 49

demostraron recientemente que el umbral de 7,5% es costo- mdicos metas y mediciones tangibles.58 Adems, quitar los
efectivo, con una proporcin de costo-efectividad incremental objetivos del tratamiento hace difcil para los pacientes me-
de $37.000 por ao ganado ajustado por calidad. jorar su perfil de riesgo (por medios no farmacolgicos) de
Adems de aumentar el nmero de adultos elegibles para manera suficiente para no justificar ms la farmacoterapia.
estatinas en los Estados Unidos, otra consecuencia importante Comenzar una medicacin preventiva sin la posibilidad de
de la disminucin del umbral de tratamiento es una reduccin discontinuar la medicacin en el futuro puede ser un desafo
en la proporcin de individuos considerados de riesgo inter- filosfico desde una perspectiva de la salud pblica porque
medio, que disminuira de 32% a 12% con la implementa- esto esencialmente medicaliza a una gran proporcin de la co-
cin plena de las guas ACC/AHA 2013.53 El tratamiento ms munidad mientras quita nfasis a la importancia potencial de
apropiado para individuos de riesgo intermedio es, por defi- modificaciones en el estilo de vida.
nicin, menos cierto; por consiguiente, el juicio clnico y los Aunque las ms recientes guas NICE de manera semejan-
estudios adicionales han sido histricamente promovidos para te acaban con los objetivos del tratamiento, las ltimas guas
definir las recomendaciones de tratamiento en este grupo. Se ESC/EAS y CCS continan aprobando las estrategias de tratar
ha enfocado un significativa atencin en el desarrollo y vali- segn un objetivo.16,18 En las guas ESC/EAS y CCS, la justifi-
dacin de biomarcadores en sangre e imgenes para mejorar cacin para continuar con el uso de los objetivos de colesterol
la precisin del riesgo estimado para estos individuos. Con la incluye una cantidad de estudios de estatinas de prevencin
disminucin del umbral de tratamiento, las guas ACC/AHA primaria y secundaria demostrando mejora de los resultados
2013 estn proponiendo que la evidencia reciente, revisada con el descenso ms intensivo de LDL.49,50,59-62 Sin embargo,
ms arriba, apoya el uso de tratamiento con estatinas en la ninguno de estos estudios utiliz objetivos de LDL especfi-
mayora de los adultos que estuvieron previamente en la cate- cos para provocar ajustes de la dosis de la medicacin, as los
gora de riesgo intermedio y por lo tanto que el grupo de indi- objetivos de LDL son extrapolados de estos estudios. Esta es
viduos en quienes el equilibrio en relacin con el tratamiento un rea altamente polmica en la que los datos de los estu-
ms adecuado ha disminuido. dios controlados aleatorizados y la prctica clnica diaria se
Las guas internacionales que hemos revisado aprueban muestran en conflicto. Se necesitan tcnicas de investigacin
fundar las decisiones de tratamiento en el riesgo de ECV ab- innovadoras para evaluar los efectos de las estrategias de tratar
soluto estimado. Sin embargo, publicaciones recientes han segn un objetivo sobre los resultados del paciente, incorpo-
sugerido potenciales modificaciones de estos mtodos. Navar- rando los efectos a corto plazo de la disminucin de lpidos y
Boggan y colegas54 han demostrado recientemente el beneficio los efectos a largo plazo relativos al bienestar del paciente y
potencial de utilizar umbrales de riesgo a 10 aos especficos que alienten conductas de estilo de vida saludables.
por edad y sexo para guiar el tratamiento, incluyendo elevar el Dos desarrollos desde la publicacin de las guas ACC/AHA
umbral de tratamiento para adultos de 66 a 75 aos de edad a 2013 pueden complicar adicionalmente el abordaje de obje-
10% en las mujeres y 15% en los hombres. Alternativamente, tivo agnstico. El primero es la publicacin de los resulta-
Ridker y colegas55 han propuesto un algoritmo hbrido que in- dos del Improved Reduction of Outcomes: Vytorin Efficacy
corporara datos de estudios clnicos dentro del algoritmo de International Trial (IMPROVE-IT), que demostr una reduc-
prevencin primaria, aunque la superioridad de esta estrategia cin del riesgo absoluto del 2% de eventos de ECV con ezeti-
es incierta.56 Estas estrategias justifican investigacin adicio- mibe aadido al tratamiento con estatinas en pacientes despus
nal para determinar si pueden utilizarse para mejorar futuras de un infarto de miocardio.10 Los individuos que recibieron la
guas de colesterol. 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
Objetivos teraputicos para el tratamiento de menos en el contexto de la prevencin secundaria. El segun-
disminucin de lpidos do desarrollo es la reciente aprobacin por la Food and Drug
Otra importante modificacin introducida por las guas Administration de EE.UU. de 2 drogas de la nueva clase de
ACC/AHA 2013 fue la remocin de los objetivos de trata- inhibidores de la proprotein-convertasa subtilisina/kexin tipo
miento especficos para el tratamiento de disminucin de lpi- 9. Mientras los estudios que evalan el impacto en los resul-
dos. En la explicacin de su base racional, el comit de la gua tados sobre la ECV severa estn en curso, estas drogas pare-
refiri la ausencia de datos de estudios clnicos que indiquen cen ser seguras y eficaces en el descenso de LDL.63 El estudio
qu objetivos precisos deberan ser, la falta de un beneficio IMPROVE-IT fue el primero en demostrar el beneficio de aa-
probado para un objetivo versus otro, la incapacidad para dar dir una medicacin no estatina en pacientes ya tratados con
cuenta de los efectos adversos o esforzarse para lograr una estatinas para prevencin secundaria. A medida que proliferan
meta dada, y la preocupacin de que las estrategias basadas en las opciones de medicaciones no estatinas para el descenso de
objetivos puedan dar como resultado un infratratamiento con LDL, los comits de guas futuras tendrn la tarea de evaluar si
estatinas o un sobretratamiento con no estatinas para alcanzar podra estar justificado un retorno a los objetivos de tratamien-
esos objetivos.11 Adicionalmente, hay pequeas pero signifi- to de LDL (por lo menos en ciertas circunstancias) para guiar
cativas diferencias entre la estimacin de la concentraciones la adicin de estas nuevas opciones farmacolgicas en ciertos
de LDL con la frmula de Friedewald y mediciones directas.57 pacientes de alto riesgo ya tratados con estatinas.64
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 Abordaje de prevencin primaria para aquellos
este abordaje agnstico del objetivo han argumentado que con diabetes mellitus o ERC
los objetivos del tratamiento son valiosos en la prctica clnica A pesar de las diferencias en el lenguaje utilizado y los deta-
y que sirven para reforzar la conducta positiva del paciente y lles acerca de la dosis de estatinas sugerida, las guas interna-
los cambios del estilo de vida y brindar a los pacientes y a sus cionales generalmente estn de acuerdo sobre el abordaje a
50 Circulation Octubre 2016

la prevencin primaria en aquellos con diabetes mellitus (la de riesgo, con el riesgo absoluto a ser calculado solamente en
Tabla 2 brinda detalles). Las diferencias notables pertenecen aquellos con dos factores de riesgo mayores. Las guas de la
mayormente al tratamiento de los pacientes <40 aos de edad, NLA consideran que el alto riesgo es un riesgo de ECV AS
en quienes hay escasa evidencia de lo apropiado del tratamien- estimado a 10 aos de 15% (utilizando las ecuaciones de la
to con estatinas para la prevencin primaria de la ECV. Cohorte Agrupada). Adems, las guas de la NLA tambin
El acuerdo entre las guas es menos uniforme para el tra- aprueban una estrategia de tratamiento segn el objetivo y
tamiento de individuos con ERC. Las guas ACC/AHA 2013 apoyan el uso de objetivos de tratamiento basados en no-HDL
son las nicas entre las guas internacionales revisadas en no como opuesto al LDL. Con estas caractersticas, las guas de
considerar la presencia de ERC para conferir alto riesgo. Las la NLA son ms similares a las guas ATP III, ESC/EAS 2011
guas ESC/EAS 2011 y CCS 2012 caracterizan a los pacien- y CCS 2012 que a las guas ACC/AHA 2013.
tes con ERC como de alto o muy alto riesgo y recomiendan
tratamiento con estatinas para lograr los objetivos apropiados Resumen
de LDL.16,18 Las guas NICE 2014 recomiendan comenzar con Las guas ACC/AHA 2013 para el tratamiento del colesterol
atorvastatina 20 mg para todos los pacientes con ERC.17 Los hacen varios cambios notables con respecto a las antiguas
documentos ACC/AHA 2013, ESC/EAS 2011, NICE 2014 y guas ATP III. De estos, los tres de mayor impacto son la in-
CCS 2012 estn de acuerdo en que no hay evidencia suficiente troduccin de las ecuaciones de la Cohorte Agrupada como la
para apoyar recomendaciones especficas para los pacientes herramienta de evaluacin de riesgo preferida, y disminuir el
con enfermedad renal de estadio terminal que reciben hemo- umbral de riesgo para la consideracin de estatinas en los cua-
dilisis regular. Aunque las guas ACC/AHA 2013 son las dros de prevencin primaria (comenzando con una discusin
nicas entre las guas internacionales revisadas en no tratar a mdico-paciente) a un riesgo de ECV AS absoluto a 10 aos
todos los individuos con ERC como de alto riesgo, utilizando de 7,5%, y quitar los objetivos del tratamiento del colesterol.
datos del estudio REGARDS, Colantonio y colegas65 demos- Despus de revisar varias guas internacionales destacadas,
traron que solamente el 8% de los individuos con ERC que observamos una falta de consenso sobre el abordaje ptimo
tienen de 50 a 79 aos de edad no calificara para la conside- de la evaluacin del riesgo, umbrales de tratamiento, o el uso
racin de tratamiento con estatinas sobre las bases de las guas de objetivos de colesterol entre estas guas. Como resultado,
ACC/AHA 2013. Por lo tanto, es incierto si esta distincin en- las recomendaciones para la prevencin primaria del trata-
tre las guas ACC/AHA 2013 y otras guas realmente afecta las miento de disminucin de lpidos para un individuo varan de
recomendaciones a nivel individual. acuerdo a cul pauta se sigue, como se ilustra por medio de
la vieta clnica. Estas observaciones subrayan la importancia
Otras guas de EE.UU. recientes de investigacin adicional enfocada a refinar los modelos de
Desde la publicacin de las guas ACC/AHA 2013, la US prediccin del riesgo y determinar las estrategias ptimas para
Preventive Services Task Force (USPSTF)48 y la National controlar y ajustar el tratamiento mdico.
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
Fuentes de fondos
Dr Nayor fue apoyado por un subsidio de entrenamiento T32-
a la prevencin primaria) y las guas ACC/AHA 2013 es en HL007604 de los National Institutes of Health y del Clinical Skills
general fuerte. Las recomendaciones de la USPSTF apoyan el Development Core Training National Heart, Lung, and Blood
uso de las ecuaciones de la Cohorte Agrupada para la evalua- Institute U10HL110337. Dr. Vasan fue apoyado por contratos del
cin del riesgo absoluto y sugieren aparear la intensidad del National Heart, Lung, and Blood Institutes Framingham Heart Study
tratamiento con estatinas al riesgo absoluto (como opuesto al N01-HC-25195 y HHSN268201500001I.
abordaje de tratamiento segn el objetivo de otras guas). Una
notable diferencia, sin embargo, es que las recomendaciones Declaracin de intereses
de la USPSTF requieren individuos que tengan un riesgo a 10 Ninguno.
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 Bibliografa
estatinas a dosis bajas a moderadas pueden considerarse para 1. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional,
individuos con factores de riesgo adicionales o despus de and national age-sex specific all-cause and cause-specific mortality for 240
causes of death, 19902013: a systematic analysis for the Global Burden of
una discusin con el paciente acerca de la reduccin del ries- Disease Study 2013. Lancet. 2015;385:117171.
go absoluto relativamente pequea esperada en este grupo.48 2. Moran AE, Tzong KY, Forouzanfar MH, Rothy GA, Mensah GA, Ezzati
Esta distincin entre la declaracin de la USPSTF y las guas M, Murray CJ, Naghavi M. Variations in ischemic heart disease burden
ACC/AHA 2013 destaca varios temas importantes previamen- by age, country, and income: the Global Burden of Diseases, Injuries,
and Risk Factors 2010 study. Glob Heart. 2014;9:9199. doi: 10.1016/j.
te elevados en esta revisin, incluyendo la incertidumbre de gheart.2013.12.007.
los mtodos de prediccin de riesgo actuales y las dificultades 3. Bloom DE, Cafiero E, Jan-Llopis E, Abrahams-Gessel S, Bloom LR,
para balancear los considerables costos y los efectos adversos Fathima S, Feigl AB, Gaziano T, Hamandi A, Mowafi M. The Global
potenciales asociados con el uso de estatinas con la pequea Economic Burden of Noncommunicable Diseases. Geneva, Switzerland:
World Economic Forum; 2011.
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