2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic

46 Pages·2014·2.16 MB·English

JournaloftheAmericanCollegeofCardiology Vol.63,No.25,2014
(cid:1)2014TheExpertPanelMembers ISSN0735-1097/$36.00
PublishedbyElsevierInc. http://dx.doi.org/10.1016/j.jacc.2013.11.002
PRACTICE GUIDELINE
2013 ACC/AHA Guideline on the
Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adultsq
A Report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines
Endorsed by the American Academy of Physician Assistants, American Association of Cardiovascular and
Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology,
Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and
WomenHeart: The National Coalition for Women With Heart Disease
ExpertPanel Neil J. Stone, MD, MACP, FAHA, FACC, Daniel Levy, MD*
Members Chair Donald M. Lloyd-Jones, MD, SCM, FACC,
Jennifer G. Robinson, MD, MPH, FAHA, FAHA
Vice Chair Patrick McBride, MD, MPH, FAHA
Alice H. Lichtenstein, DSC, FAHA, Vice Chair J. Sanford Schwartz, MD
Susan T. Shero, MS, RN*
C. Noel Bairey Merz, MD, FAHA, FACC Sidney C. Smith, JR, MD, FACC, FAHA
Conrad B. Blum, MD, FAHA Karol Watson, MD, PHD, FACC, FAHA
Robert H. Eckel, MD, FAHA Peter W. F. Wilson, MD, FAHA
Anne C. Goldberg, MD, FACP, FAHA
David Gordon, MD* *Ex-OfficioMembers.
Methodology KarenM.Eddleman,BS LevNevo,MD
Members NicoleM.Jarrett JanuszWnek,PHD
KenLaBresh,MD
ACC/AHATask JeffreyL.Anderson,MD,FACC,FAHA,Chair David DeMets, PHD
ForceMembers Jonathan L. Halperin, MD, FACC, FAHA, Judith S. Hochman, MD, FACC, FAHA
Chair-Elect Richard J. Kovacs, MD, FACC, FAHA
E. Magnus Ohman, MD, FACC
NancyM.Albert,PHD,CCNS,CCRN,FAHA Susan J. Pressler, PHD, RN, FAAN, FAHA
Biykem Bozkurt, MD, PHD, FACC, FAHA Frank W. Sellke, MD, FACC, FAHA
Ralph G. Brindis, MD, MPH, MACC Win-Kuang Shen, MD, FACC, FAHA
Lesley H. Curtis, PHD, FAHA
Subcommitteeon SidneyC.Smith,JR,MD,FACC,FAHA,Chair GordonF.Tomaselli,MD,FACC,FAHA,Co-Chair
Prevention
Guidelines
q
The Journal of the American College of Cardiology is published on behalf of TheAmericanCollegeofCardiologyrequeststhatthisdocumentbecitedasfol-
the American College of Cardiology Foundation by Elsevier Inc.; Circulation lows:StoneNJ,RobinsonJG,LichtensteinAH,BaireyMerzCN,BlumCB,Eckel
is published on behalf of the American Heart Association, Inc., by Wolters RH,GoldbergAC,GordonD,LevyD,Lloyd-JonesDM,McBrideP,SchwartzJS,
Kluwer.ThisisanopenaccessarticleunderthetermsoftheCreativeCommons SheroST,SmithSCJr,WatsonK,WilsonPWF.2013ACC/AHAguidelineonthe
AttributionNon-Commercial-NoDervisLicense, whichpermits use, distribu- treatmentofbloodcholesteroltoreduceatheroscleroticcardiovascularriskinadults:a
tion, and reproduction in any medium, provided that the Contribution is reportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTask
properlycited,theuseisnoncommercial,andnomodificationsoradaptations ForceonPracticeGuidelines.JAmCollCardiol2014;63:2889–934.
aremade. ThisarticleiscopublishedinCirculation.
ThisdocumentwasapprovedbytheAmericanCollegeofCardiologyBoardof Copies:ThisdocumentisavailableontheWorldWideWebsitesoftheAmerican
TrusteesandtheAmericanHeartAssociationScienceAdvisoryandCoordinating CollegeofCardiology(http://www.cardiosource.org)andtheAmericanHeartAs-
CommitteeinNovember2013.TheAcademyofNutritionandDieteticsaffirmsthe sociation(my.americanheart.org).Forcopiesofthisdocument,pleasecontactthe
valueofthisguideline. ElsevierInc.ReprintDepartment,fax[phone],[email protected].
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8. Limitations ...................................2914
TABLEOFCONTENTS
PreambleandTransitiontoACC/AHAGuidelinesto 9. EvidenceGapsandFutureResearch Needs ..2914
ReduceCardiovascular Risk ......................2890
10. Conclusions .................................2914
1. Introduction ..................................2891
References........................................2915
1.1. OrganizationofthePanel ................ 2891
1.2. DocumentReviewandApproval .......... 2891 Appendix 1. AuthorRelationships With Industry
1.3. ScopeofGuideline ....................... 2892 andOtherEntities (Relevant) .....................2919
1.4. MethodologyandEvidenceReview ....... 2894
Appendix 2. ExpertReviewerRelationships With
2. Overview ofthe Guideline ....................2895 Industry andOtherEntities .......................2922
2.1. LifestyleastheFoundationfor
Appendix 3. Abbreviations ........................2923
ASCVDRisk-ReductionEfforts ............ 2895
2.2. InitiationofStatinTherapy ............... 2897
Appendix 4. EvidenceStatements ................2923
3. Critical QuestionsandConclusions...........2897
Appendix 5. ExpandedDiscussionof
3.1. IdentificationofCQs ..................... 2897 What’s NewintheGuideline ......................2932
3.1.1. CQ1:LDL-CandNon–HDL-CGoalsin
SecondaryPrevention ................. 2899
3.1.2. CQ2:LDL-CandNon–HDL-CGoalsin
PrimaryPrevention ................... 2899
3.1.3. CQ3:EfficacyandSafetyof Preamble and Transition to ACC/AHA
Cholesterol-LoweringMedications ..... 2899 Guidelines to Reduce Cardiovascular Risk
4. StatinTreatment: Recommendations.........2899
The goals of the American College of Cardiology (ACC)
4.1. IntensityofStatinTherapyinPrimaryand
andtheAmericanHeartAssociation(AHA)aretoprevent
SecondaryPrevention .................... 2899
4.2. LDL-CandNon–HDL-CTreatmentGoals.... 2901 cardiovasculardiseases;improvethemanagementofpeople
who have these diseases through professional education
4.3. SecondaryPrevention .................... 2902
and research; and develop guidelines, standards, and pol-
4.4. PrimaryPreventioninIndividuals‡21Yearsof
icies that promote optimal patient care and cardiovascular
AgeWithLDL-C‡190mg/dL.............. 2903
health.Towardtheseobjectives,theACCand AHAhave
4.5. PrimaryPreventioninIndividualsWith
collaborated with the National Heart, Lung, and Blood
Diabetes ................................. 2905
Institute (NHLBI) and stakeholder and professional or-
4.6. PrimaryPreventioninIndividualsWithout
ganizations to develop clinical practice guidelines for
DiabetesandWithLDL-C70to189mg/dL 2905
assessment of cardiovascular risk, lifestyle modifications to
4.7. RiskAssessmentinPrimaryPrevention... 2906
reduce cardiovascular risk, management of blood choles-
4.8. HeartFailureandHemodialysis ........... 2907
terolinadults,andmanagementofoverweightandobesity
5. Safety: Recommendations ...................2907 in adults.
In 2008, the NHLBI initiated these guidelines by
6. Managing StatinTherapy: sponsoring rigorous systematic evidence reviews for each
Recommendations............................2911 topic by expert panels convened to develop critical ques-
tions (CQs), interpret the evidence, and craft recommen-
6.1. MonitoringStatinTherapy ................ 2911 dations. In response to the 2011 report from the Institute
6.2. OptimizingStatinTherapy ................ 2912 of Medicine on the development of trustworthy clinical
6.3. InsufficientResponsetoStatinTherapy .. 2912 guidelines (1), the NHLBI Advisory Council recom-
6.3.1. Testing ............................. 2912 mended that the NHLBI focus specifically on reviewing
6.3.2. NonstatinsAddedtoStatinsorin the highest-quality evidence and partner with other orga-
Statin-IntolerantIndividuals ........... 2913 nizations to develop recommendations (2,3). Accordingly,
7. Selected ClinicalandPopulation in June 2013 the NHLBI initiated collaboration with the
Subgroups ....................................2913 ACC and AHA to work with other organizations to
complete and publish the 4 guidelines noted above and
7.1. SexandRacialandEthnicSubgroups..... 2913 make them available to the widest possible constituency.
7.2. Individuals>75YearsofAge ............. 2913 RecognizingthattheExpertPanels/WorkGroupsdidnot
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consider evidence beyond 2011 (except as specified in the NHLBI. The guideline was reviewed by the ACC/
methodology),theACC,AHA,andcollaboratingsocieties AHA Task Force and approved by the ACC Board
plan to begin updating these guidelines starting in 2014. of Trustees, and the AHA Science Advisory and Coor-
The joint ACC/AHA Task Force on Practice Guide- dinating Committee. In addition, ACC/AHA sought
lines (Task Force) appointed a subcommittee to shepherd endorsement from other stakeholders, including profes-
thistransition,communicatetherationaleandexpectations sional organizations. It is the hope of the writing panels,
to the writing panels and partnering organizations, and stakeholders, professional organizations, NHLBI, and
expeditiouslypublishthedocuments.TheACC/AHAand Task Force that the guidelines will garner the widest
partner organizations recruited a limited number of expert possible readership for the benefit of patients, providers,
reviewersforfiduciaryexaminationofcontent,recognizing and the public health.
that each document had undergone extensive peer review These guidelines are meant to define practices that
by representatives of the NHLBI Advisory Council, key meet the needs of patients in most circumstances and
federal agencies, and scientific experts. Each writing panel are not a replacement for clinical judgment. The ulti-
responded to comments from these reviewers. Clarifica- matedecisionaboutcareofaparticularpatientmustbe
tions were incorporated where appropriate, but there were made by the healthcare provider and patient in light of
nosubstantivechangesbecausethebulkofthecontentwas thecircumstancespresentedbythatpatient.Asaresult,
undisputed. situations might arise in which deviations from these
Although the Task Force led the final development of guidelines may be appropriate. These considerations
these prevention guidelines, they differ from other ACC/ notwithstanding, in caring for most patients, clinicians
AHA guidelines. First, as opposed to an extensive com- canemploy therecommendationsconfidentlyto reduce
pendium of clinical information, these documents are the risks of atherosclerotic cardiovascular disease
significantly more limited in scope and focus on selected (ASCVD) events.
CQs on each topic, based on the highest-quality evidence SeeTables1a and1bforanexplanationoftheNHLBI
available.Recommendationswerederivedfromrandomized recommendation grading methodology.
trials,meta-analyses,andobservationalstudiesevaluatedfor
quality and were not formulated when sufficient evidence 1. Introduction
was not available. Second, the text accompanying each
recommendationis succinct,summarizingtheevidencefor
1.1. Organization of the Panel
eachquestion.TheFullPanel/WorkGroupReportsinclude
more detailed information about the evidence statements The Blood Cholesterol Expert Panel (Expert Panel) was
that serve as the basis for recommendations. Third, the originally convened as the Expert Panel on Detection,
format of the recommendations differs from other ACC/ Evaluation, and Treatment of High Blood Cholesterol
AHA guidelines.Eachrecommendation has beenmapped in Adults (Adult Treatment Panel IV) appointed by
fromtheNHLBIgradingformattotheACC/AHAClas- the NHLBI. The Expert Panel was composed of 13
sification of Recommendation/Level of Evidence (COR/ members and 3 ex-officio members, which included pri-
LOE)construct(Table1)andisexpressedinbothformats. mary care physicians, cardiologists, endocrinologists, and
Becauseoftheinherentdifferencesingradingsystemsand experts in clinical lipidology, clinical trials, cardiovascular
the clinical questions driving the recommendations, align- epidemiology and nutrition, and guideline development.
ment between the NHLBI and ACC/AHA formats is in TheExpertPanelchairaskedallpanelmemberstodisclose
some cases imperfect. Explanations of these variations are any conflict-of-interest information to the full panel in
notedintherecommendationtables,whereapplicable. advance of the deliberations; members with conflicts were
In consultation with NHLBI, the policies adopted by asked to recuse themselves from voting on any aspect
thewritingpanels tomanagerelationships of authorswith of the guideline for which a conflict might exist. All 16
industry and other entities (RWI) are outlined in the membersoftheNHLBIAdultTreatmentPanelIVPanel
methods section of each panel report. These policies were transitioned to the ACC/AHA guideline Expert Panel.
in effect when this effort began in 2008 and throughout Independent contractors performed the systematic review
the writing process and voting on recommendations, until with the assistance of the Expert Panel and provided
theprocesswastransferredtoACC/AHAin2013.Inthe methodological guidance to the Expert Panel.
interest of transparency, the ACC/AHA requested that
1.2. Document Review and Approval
panel authors resubmit RWI disclosures as of July 2013.
Relationships relevant to this guideline are disclosed in Aformalpeerreviewprocesswasinitiallycompletedunder
Appendix1.NoneoftheACC/AHAexpertreviewershad the auspices of the NHLBI and included 23 expert re-
relevant RWI (Appendix 2). See Appendix 3 for a list of viewers and representatives of federal agencies. This doc-
abbreviations used in the guideline. ument was also reviewed by 4 expert reviewers nominated
Systematic evidence reports and accompanying sum- by the ACC and the AHA when the management of the
mary tables were developed by the expert panels and guideline transitioned to the ACC/AHA. The ACC and
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Table1. ApplyingClassificationofRecommendationandLevelofEvidence
ArecommendationwithLevelofEvidenceBorCdoesnotimplythattherecommendationisweak.Manyimportantclinicalquestionsaddressedintheguidelinesdonotlendthemselvestoclinicaltrials.
Evenwhenrandomizedtrialsareunavailable,theremaybeaveryclearclinicalconsensusthataparticulartestortherapyisusefuloreffective.
*Dataavailablefromclinicaltrialsorregistriesabouttheusefulness/efficacyindifferentsubpopulations,suchassex,age,historyofdiabetes,historyofpriormyocardialinfarction,historyofheart
failure,andprioraspirinuse.
yForcomparative-effectivenessrecommendations(ClassIandIIa;LevelofEvidenceAandBonly),studiesthatsupporttheuseofcomparatorverbsshouldinvolvedirectcomparisonsofthetreatments
orstrategiesbeingevaluated.
AHA reviewers’ RWI information is published in this guideline.TheFullPanelReportcontainsbackgroundand
document (Appendix 2). additional material related to content, methodology, evi-
This document was approved for publication by the dence synthesis, rationale, and references and is supported
governing bodies of the ACC and AHA and endorsed by bytheNHLBISystematicEvidenceReview,whichcanbe
theAmericanAcademyofPhysicianAssistants,American foundathttp://www.nhlbi.nih.gov/guidelines/cholesterol/ser/.
Association of Cardiovascular and Pulmonary Rehabilita- Table 2 provides an overview to facilitate understanding
tion,AmericanPharmacistsAssociation,AmericanSociety what is new in the present guideline.
for Preventive Cardiology, Association of Black Cardiol- The Expert Panel was charged with using data from
ogists, Preventive Cardiovascular Nurses Association, and randomizedcontrolledtrials(RCTs)andsystematicreviews
WomenHeart: The National Coalition for Women with and meta-analyses of RCTs to update the clinical practice
Heart Disease. recommendations for the treatment of blood cholesterol
levels to reduce ASCVD risk. For this guideline, ASCVD
1.3. Scope of Guideline
includes coronary heart disease (CHD), stroke, and pe-
This guideline is based on the Full Panel Report, which ripheral arterial disease, all of presumed atherosclerotic
is provided as an online-only data supplement to the origin. These recommendations are intended to provide a
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Table1a. NHLBIGradingoftheStrengthof Table1b. NHLBIQualityRatingoftheStrengthofEvidence
Recommendations
TypeofEvidence QualityRating*
Grade StrengthofRecommendation* (cid:3) Well-designed,well-executedyRCTthatadequately High
A Strongrecommendation representpopulationstowhichtheresultsareapplied
Thereishighcertaintybasedonevidencethatthenetbenefity anddirectlyassesseffectsonhealthoutcomes.
issubstantial. (cid:3) Meta-analysesofsuchstudies.
B Moderaterecommendation Highlycertainabouttheestimateofeffect.Further
Thereismoderatecertaintybasedonevidencethatthenetbenefitis researchisunlikelytochangeourconfidenceinthe
moderatetosubstantial,orthereishighcertaintythatthenet estimateofeffect.
benefitismoderate. (cid:3) RCTwithminorlimitationszaffectingconfidencein, Moderate
C Weakrecommendation orapplicabilityof,theresults.
Thereisatleastmoderatecertaintybasedonevidencethatthereisa (cid:3) Well-designed,well-executednonrandomizedcontrolled
smallnetbenefit. studiesxandwell-designed,well-executedobservational
D Recommendationagainst studiesk.
Thereisatleastmoderatecertaintybasedonevidencethat (cid:3) Meta-analysesofsuchstudies.
thereisnonetbenefitorthatrisks/harmsoutweighbenefits. Moderatelycertainabouttheestimateofeffect.Further
E Expertopinion(“Thereisinsufficientevidenceorevidenceis researchmayhaveanimpactonourconfidenceinthe
unclearorconflicting,butthisiswhattheWorkGroup estimateofeffectandmaychangetheestimate.
recommends.”) (cid:3) RCTwithmajorlimitations. Low
Netbenefitisunclear.Balanceofbenefitsandharmscannotbe (cid:3) Nonrandomized controlled studies and observational
determinedbecauseofnoevidence,insufficientevidence, studieswithmajorlimitationsaffectingconfidencein,
unclearevidence,orconflictingevidence,buttheWorkGroup orapplicabilityof,theresults.
thoughtitwasimportanttoprovideclinicalguidanceand (cid:3) Uncontrolledclinicalobservationswithoutanappropriate
makearecommendation.Furtherresearchisrecommended comparisongroup(e.g.,caseseries,casereports).
inthisarea. (cid:3) Physiologicalstudiesinhumans.
N Norecommendationfororagainst(“Thereisinsufficientevidenceor (cid:3) Meta-analysesofsuchstudies.
evidenceisunclearorconflicting.”) Lowcertaintyabouttheestimateofeffect.Further
Netbenefitisunclear.Balanceofbenefitsandharmscannotbe researchislikelytohaveanimpactonourconfidence
determinedbecauseofnoevidence,insufficientevidence,unclear intheestimateofeffectandislikelytochangethe
evidence,orconflictingevidence,andtheWorkGroupthought estimate.
norecommendationshouldbemade.Furtherresearchis
*Insomecases,otherevidence,suchaslargeall-or-nonecaseseries(e.g.,jumpingfromair-
recommendedinthisarea.
planesortallstructures),canrepresenthigh-ormoderate-qualityevidence.Insuchcases,the
rationalefortheevidenceratingexceptionshouldbeexplainedbytheWorkGroupandclearly
*Inmostcases,thestrengthoftherecommendationshouldbecloselyalignedwiththequality justified.
oftheevidence;however,undersomecircumstances,theremaybevalidreasonsformaking y“Well-designed, well-executed” refers to studies that directly address the question; use
recommendationsthatarenotcloselyalignedwiththequalityoftheevidence(e.g.,strong adequaterandomization,blinding,andallocationconcealment;areadequatelypowered;use
recommendationwhentheevidencequalityismoderate,suchassmokingcessationtoreduce intention-to-treatanalyses;andhavehighfollow-uprates.
cardiovasculardiseaseriskororderinganECGaspartoftheinitialdiagnosticwork-upfora zLimitationsincludeconcernswiththedesignandexecutionofastudythatresultindecreased
patientpresentingwithpossibleMI).Thosesituationsshouldbelimitedandtherationale confidenceinthetrueestimateoftheeffect.Examplesofsuchlimitationsincludebutarenot
explainedclearlybytheWorkGroup. limitedto:inadequaterandomization,lackofblindingofstudyparticipantsoroutcomeasses-
yNetbenefitisdefinedasbenefitsminusrisks/harmsoftheservice/intervention. sors,inadequatepower,outcomesofinterestthatarenotprespecifiedfortheprimaryout-
ECGindicateselectrocardiogram;MI,myocardialinfarction;andNHLBI,NationalHeart,Lung, comes,lowfollow-uprates,andfindingsbasedonsubgroupanalyses.Whetherthelimitations
andBloodInstitute. areconsideredminorormajorisbasedonthenumberandseverityofflawsindesignor
execution.Rulesfordeterminingwhetherthelimitationsareconsideredminorormajorandhow
theywillaffectratingoftheindividualstudieswillbedevelopedcollaborativelywiththemeth-
strong, evidence-based foundation for the treatment of odologyteam.
xNonrandomizedcontrolledstudiesrefertointerventionstudieswhereassignmenttointer-
cholesterol for the primary and secondary prevention of ventionandcomparisongroupsisnotrandom(e.g.,quasi-experimentalstudydesign).
ASCVD in women and men. jjObservationalstudiesincludeprospectiveandretrospectivecohort,case-control,andcross-
sectionalstudies.
BecauseRCTdatawereusedtoidentifythosemostlikely NHLBIindicatesNationalHeart,Lung,andBloodInstitute;andRCT,randomizedcontrolled
to benefit from cholesterol-lowering statin therapy, the trials.
recommendationswillbeofvaluetoprimarycareclinicians
as well as specialists concerned with ASCVD prevention. cholesterol (LDL-C) levels with greater ASCVD risk.
Importantly, the recommendations were designed to be These studies provided the rationale for RCTs, which in
easy to use in the clinical setting, facilitating the imple- turndemonstrated thatloweringcholesterollevelsreduced
mentation of a strategy of risk assessment and treatment ASCVD events and thereby established a central, causal
focused on the prevention of ASCVD. The present role of atherogenic cholesterol-containing lipoprotein
guideline is intended to address treatment of adults ((cid:2)21 particles, particularly LDL, in the genesis of CHD and
years of age) to complement the NHLBI cardiovascular ASCVD.
health risk-reduction guideline for children and adoles- Other strategies for using drug therapy to reduce
cents (4). ASCVD events have been advocated, including treat-
The members of the Expert Panel acknowledge the to-cholesterol target, lowest-is-best, and risk-based treat-
important contributions arising from decades of genetic ment approaches. However, only 1 approach has been
and biochemical studies, observational epidemiological evaluated in multiple RCTsdthe use of fixed doses of
and ecological studies, and in vitro and animal experi- cholesterol-loweringdrugstoreduceASCVDrisk.Because
ments that associated higher low-density lipoprotein the overwhelming body of evidence came from statin
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Table2. What’sNewintheGuideline?* evaluation,andtreatmentoflipiddisordersaswasdonein
thepriorAdultTreatmentPanelIIIReport(6).However,
1 FocusonASCVDRiskReduction:4StatinBenefitGroups
1. ThisguidelineisbasedonacomprehensivesetofdatafromRCTs the present guideline was never intended to be a compre-
fromwhich4statinbenefitgroupswereidentifiedthatfocusefforts
hensive approach to lipid management for purposes other
toreduceASCVDeventsinsecondaryandprimaryprevention.
2. Thisguidelineidentifieshigh-intensityandmoderate-intensity than ASCVD risk reduction. A limited number of expert
statintherapyforuseinsecondaryandprimaryprevention. opinion recommendations were made only when RCT
2 ANewPerspectiveonLDL-Cand/orNon–HDL-CTreatmentGoals evidence was not present and after a thorough consider-
1. TheExpertPanelwasunabletofindRCTevidencetosupport
ation of what the Expert Panel had learned from the
continueduseofspecificLDL-Cornon–HDL-Ctreatmenttargets.
2. Theappropriateintensityofstatintherapyshouldbeusedto RCTs. For the many questions about complex lipid dis-
reduceASCVDriskinthosemostlikelytobenefit. ordersthatarebeyondthescopeofoursystematicevidence
3. Nonstatintherapies,ascomparedwithstatintherapy, review, or for which little or no RCT data are available, it
donotprovideacceptableASCVDrisk-reductionbenefitsrelative
is anticipated that clinicians with lipid expertise can
totheirpotentialforadverseeffectsintheroutineprevention
ofASCVD. contribute to their management.
3 GlobalRiskAssessmentforPrimaryPrevention
1. ThisguidelinerecommendsuseofthenewPooledCohortEquations
1.4. Methodology and Evidence Review
toestimate10-yearASCVDriskinbothwhiteandblackmenand
women. Although the Expert Panel was convened before the
2. Bymoreaccuratelyidentifyinghigher-riskindividualsforstatin
Institute of Medicine reports on practice guidelines, our
therapy,theguidelinefocusesstatintherapyonthosemostlikely
tobenefit. evidence-based process followed most of the standards
3. Italsoindicates,onthebasisofRCTdata,thosehigh-riskgroups from the Institute of Medicine report, “Clinical Practice
thatmightnotbenefit. GuidelinesWeCanTrust”(1).Thesystematicreviewwas
4. Thisguidelinerecommendsadiscussionbetweenclinicians
limited to RCTs with ASCVD outcomes and systematic
andpatientsbeforeinitiationofstatintherapy.
reviews and meta-analyses of RCTs with ASCVD out-
4 SafetyRecommendations
1. ThisguidelineusedRCTstoidentifyimportantsafety comes. Observational studies and those with <18 months
considerationsinindividualsreceivingtreatmentofblood (CQ1andCQ2)or<12months(CQ3)offollow-upwere
cholesteroltoreduceASCVDrisk.
2. UsingRCTstodeterminestatinadverseeffectsfacilitates excluded. Support was provided by a methodology con-
understandingofthenetbenefitfromstatintherapy. tractor and a systematic review and general support con-
3. Thisguidelineprovidesexpertguidanceonmanagementof tractor and included the following steps:
statin-associatedadverseeffects,includingmusclesymptoms.
5 RoleofBiomarkersandNoninvasiveTests (cid:3) The Expert Panel constructed CQs relevant to
1. Treatmentdecisionsinselectedindividualswhoarenotincluded
clinical practice.
inthe4statinbenefitgroupsmaybeinformedbyotherfactorsas
recommendedbytheRiskAssessmentWorkGroupand (cid:3) The Expert Panel identified (a priori) inclusion/
BloodCholesterolExpertPanel. exclusion criteria for each CQ.
6 FutureUpdatestotheBloodCholesterolGuideline (cid:3) An independent contractor developed a literature
1. Thisisacomprehensiveguidelinefortheevidence-basedtreatment
search strategy, based oninclusion/exclusion criteria,
ofbloodcholesteroltoreduceASCVDrisk.
2. Futureupdateswillbuildonthisfoundationtoprovideexpert for each CQ.
guidanceonthemanagementofcomplexlipiddisordersand (cid:3) An independent contractor executed a systematic
incorporaterefinementsinriskstratificationbasedoncritical
electronic search of the published literature from
reviewofemergingdata.
relevant bibliographic databases for each CQ. The
3. RCTscomparingalternativetreatmentstrategiesareneededin
ordertoinformfutureevidence-basedguidelinesfortheoptimum date range for the overall literature search was
ASCVDrisk-reductionapproach. January 1, 1995, through December 1, 2009. How-
ever, RCTs with hard ASCVD outcomes of myo-
*SeeAppendix5,foranexpandeddiscussionofwhat’snewintheguideline.
ASCVD indicates atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cardial infarction (MI), stroke, and cardiovascular
cholesterol;LDL-C,low-densitylipoproteincholesterol;andRCT,randomizedcontrolledtrial.
death published after that date range were eligible
for consideration until the Expert Panel began de-
RCTs, the Expert Panel appropriately focused on these liberations on relevant recommendations.
statin RCTs to develop evidence-based guidelines for the (cid:3) RCTs that met the inclusion criteria and were
reduction of ASCVD risk. We recognize that this repre- independently graded as fair or good quality were
sents a significant departure from current strategies. This included in the evidence tables for the consideration
should not come as a surprise to clinicians. The recent oftheExpertPanel.RCTsthatweregraded aspoor
guidelineonheartfailurehaschangedlong-standingpara- quality were excluded.
digmsonthebasisoftheevidence,andthisguidelinedoes (cid:3) With the assistance of independent methodologists,
as well (5). Future RCTs will be needed to determine the this evidence base was used to develop a series of
optimaltreatmentstrategytoprovidethegreatestreduction evidence statements graded on the level of the evi-
inASCVDeventswithbestmarginofsafety. dence (high, medium, or low).
TheExpertPanelacknowledgesthatourprocessdidnot (cid:3) TheExpertPanelthensynthesizedtheevidencestate-
provide for a comprehensive approach to the detection, ments into treatment recommendations/summaries
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graded as A (strong), B (moderate), C (weak), D Therefore, the Expert Panel was unable to find RCT
(recommend against), E (expert), and N (no evidence to support titrating cholesterol-lowering drug
recommendation). therapy to achieve target LDL-C or non–HDL-C levels,
(cid:3) The final evidence statements and treatment rec- as recommended by Adult Treatment Panel III (6–8).
ommendations were approved by at least a majority Notably,theExpertPaneldidfindRCTevidencethatuse
of voting members of the Expert Panel. oftherapy(e.g.,niacin)toadditionallylowernon–HDL-C,
(cid:3) Guideline implementability appraisals, planned and once an LDL-C target was achieved, did not further
coordinated by the NHLBI Implementation Work reduce ASCVD outcomes (9). The Expert Panel also
Group, were performed to identify and address bar- found extensive RCT evidence that the appropriate in-
riers to guideline implementation. tensity of statin therapy should be used to reduce
ASCVDriskinthosemostlikelytobenefit.Theworkof
In addition, the Expert Panelwas able to include major
the Expert Panel was informed by the reports of the
RCTs and meta-analyses of RCTs publishedthrough July
Lifestyle Management (10) and Risk Assessment Work
2013 in our discussion and as part of the process of
Groups (11) (Figure 1). A summary of the major rec-
determining ACC/AHA grading of the NHLBI expert-
ommendationsforthetreatmentofcholesteroltoreduce
level recommendations.
ASCVD risk is provided in Table 3.
2. Overview of the Guideline
2.1. Lifestyle as the Foundation for
The RCTs identified in the systematic evidence review ASCVD Risk-Reduction Efforts
indicated a consistent reduction in ASCVD events from It must be emphasized that lifestyle modification (i.e.,
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhib- adhering to a heart-healthy diet, regular exercise habits,
itor (statin) therapy in secondary- and primary-prevention avoidance of tobacco products, and maintenance of a
populations, with the exception of no ASCVD event healthy weight) remains a crucial component of health
reduction when statin therapy was initiated in those with promotionandASCVDriskreduction,bothpriortoandin
NewYorkHeartAssociationclassIItoIVheartfailureor concertwiththeuseofcholesterol-loweringdrugtherapies.
those receiving maintenance hemodialysis. The RCTs Healthy diet or lifestyle modifications were recommended
either compared fixed doses of statins with placebo or as background therapy for the RCTs of cholesterol-
untreated controls, or compared fixed doses of higher- lowering drug therapy. See the “2013 AHA/ACC Guide-
intensity statins with moderate-intensity statins. These line on Lifestyle Management to Reduce Cardiovascular
trials were not designed to evaluate the effect of titrated Risk”(10)forlifestylerecommendationsforhealthyadults.
(dose-adjusted) statin treatment to achieve prespecified Drug therapy for lifestyle-related risk factors such as hy-
LDL-C or non–HDL-C goals. pertensionisoftenneededandsmokingshouldbeavoided.
Figure1. OverviewoftheExpertPanel’sGuideline
RCTsindicatesrandomizedcontrolledtrials.
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Table3. SummaryofKeyRecommendationsfortheTreatmentofBloodCholesteroltoReduceASCVDRiskinAdults
(SeeTables4,8,9,and10forthecompleterecommendations;andTable5fordefinitionofstatinintensity)
Recommendations ACC/AHACOR ACC/AHALOE
A.Heart-healthylifestylehabitsshouldbeencouragedforallindividuals
B.Theappropriateintensityofstatintherapyshouldbeinitiatedorcontinued:
1.ClinicalASCVD*
a.Age(cid:4)75yandnosafetyconcerns:High-intensitystatin I A
b.Age>75yorsafetyconcerns:Moderate-intensitystatin I A
2.Primaryprevention–PrimaryLDL-C‡190mg/dL
a.Ruleoutsecondarycausesofhyperlipidemia(Table6) I B
b.Age(cid:2)21y:High-intensitystatin I B
c.Achieveatleasta50%reductioninLDL-C IIa B
d.LDL-CloweringnonstatintherapymaybeconsideredtofurtherreduceLDL-C IIb C
3.PrimarypreventiondDiabetes40–75yearsofageandLDL-C70–189mg/dL
a.Moderate-intensitystatin I A
b.Considerhigh-intensitystatinwhen(cid:2)7.5%10-yASCVDriskusingthePooledCohortEquationsy IIa B
4.Primaryprevention–Nodiabetes40–75yearsofageandLDL-C70–189mg/dL
a.Estimate10-yASCVDriskusingtheRiskCalculatorbasedonthePooledCohortEquationsyinthoseNOTreceivingastatin; I B
estimateriskevery4–6y
b.Todeterminewhethertoinitiateastatin,engageinaclinician-patientdiscussionofthepotentialforASCVDriskreduction, IIa C
adverseeffects,drug–druginteractions,andpatientpreferences
c.Re-emphasizeheart-healthylifestylehabitsandaddressotherriskfactors
i.‡7.5%10-yASCVDrisk:Moderate-orhigh-intensitystatin I A
ii.5to<7.5%10-yASCVDrisk:Considermoderate-intensitystatin IIa B
iii.Otherfactorsmaybeconsideredz:LDL-C(cid:2)160mg/dL,familyhistoryofprematureASCVD,hs-CRP(cid:2)2.0mg/L, IIb C
CACscore(cid:2)300Agastonunits,ABI<0.9,orlifetimeASCVDrisk
5.PrimarypreventionwhenLDL-C<190mg/dLandage<40or>75y,or<5%10-yASCVDrisk IIb C
a.Statintherapymaybeconsideredinselectedindividualsz
6.StatintherapyisnotroutinelyrecommendedforindividualswithNYHAclassII-IVheartfailureorwhoarereceiving
maintenancehemodialysis
C.Regularlymonitoradherencetolifestyleanddrugtherapywithlipidandsafetyassessments
1.Assessadherence,responsetotherapy,andadverseeffectswithin4–12wkfollowingstatininitiationorchangeintherapy I A
a.Measureafastinglipidpanel I A
b.DonotroutinelymonitorALTorCKunlesssymptomatic IIa C
c.Screenandtreattype2diabetesaccordingtocurrentpracticeguidelines.Heart-healthylifestylehabitsshouldbeencouraged I B
topreventprogressiontodiabetes
d.Anticipatedtherapeuticresponse:approximately(cid:2)50%reductioninLDL-Cfrombaselineforhigh-intensitystatinand IIa B
30%to<50%formoderate-intensitystatin
i.InsufficientevidenceforLDL-Cornon–HDL-CtreatmenttargetsfromRCTs
ii.ForthosewithunknownbaselineLDL-C,anLDL-C<100mg/dLwasobservedinRCTsofhigh-intensitystatintherapy
e.Lessthananticipatedtherapeuticresponse:
i.Reinforceimprovedadherencetolifestyleanddrugtherapy I A
ii.Evaluateforsecondarycausesofhyperlipidemiaifindicated(Table6) I A
iii.Increasestatinintensity,orifonmaximally-toleratedstatinintensity,consideradditionofnonstatintherapyinselected IIb C
high-riskindividualsx
f.Regularlymonitoradherencetolifestyleanddrugtherapyevery3–12moonceadherencehasbeenestablished.Continue I A
assessmentofadherenceforoptimalASCVDriskreductionandsafety
D.Inindividualsintolerantoftherecommendedintensityofstatintherapy,usethemaximallytoleratedintensityof I B
statin.
1.Iftherearemuscleorothersymptoms,establishthattheyarerelatedtothestatin IIa B
2.Forspecificrecommendationsonmanagingmusclesymptoms(Table8)
*ClinicalASCVDincludesacutecoronarysyndromes,historyofMI,stableorunstableangina,coronaryorotherarterialrevascularization,stroke,TIA,orperipheralarterialdiseasepresumedtobeof
atheroscleroticorigin.
yEstimated10-yearor“hard”ASCVDriskincludesfirstoccurrenceofnonfatalMI,CHDdeath,andnonfatalandfatalstrokeasusedbytheRiskAssessmentWorkGroupindevelopingthePooledCohort
Equations(http://my.americanheart.org/cvriskcalculatorandhttp://www.cardiosource.org/en/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/2013-Prevention-Guideline-Tools.aspx).
zThesefactorsmayincludeprimaryLDL-C(cid:2)160mg/dLorotherevidenceofgenetichyperlipidemias;familyhistoryofprematureASCVDwithonset<55yearsofageinafirst-degreemalerelativeor<65
yearsofageinafirst-degreefemalerelative;hs-CRP(cid:2)2mg/L;CACscore(cid:2)300Agatstonunitsor(cid:2)75thpercentileforage,sex,andethnicity(foradditionalinformation,seehttp://www.mesa-nhlbi.org/
CACReference.aspx);ABI<0.9;orlifetimeriskofASCVD.Additionalfactorsthatmightaidinindividualriskassessmentcouldbeidentifiedinthefuture.
xHigh-riskindividualsincludethosewithclinicalASCVD,anuntreatedLDL-C(cid:2)190mg/dLsuggestinggenetichypercholesterolemia,orindividualswithdiabetes40to75yearsofageandLDL-C70to
189mg/dL.
ABIindicatesankle-brachialindex;ACC,AmericanCollegeofCardiology;AHA,AmericanHeartAssociation;ALT,alanineaminotransferase,atestofhepaticfunction;ASCVD,atheroscleroticcardiovascular
disease;CAC,coronaryarterycalcium;CHD,coronaryheartdisease;CK,creatinekinase,atestofmuscleinjury;COR,ClassofRecommendation;HDL-C,high-densitylipoproteincholesterol;hs-CRP,high-
sensitivityC-reactiveprotein;LDL-C,low-densitylipoproteincholesterol;LOE,LevelofEvidence;NHLBI,NationalHeart,Lung,andBloodInstitute;NYHA,NewYorkHeartAssociation;RCTs,randomized
controlledtrials;andTIA,transientischemicattack.
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2.2. Initiation of Statin Therapy should be used to guide the initiation of statin therapy.
The 10-year ASCVD risk should be estimated with the
TheExpertPanelfoundextensiveandconsistentevidence
Pooled Cohort Equations (Section 4.7). For the primary
supportingtheuseofstatinsforthepreventionofASCVD
prevention of ASCVD in individuals with diabetes
inmanyhigher-riskprimary-andallsecondary-prevention
(diabetes mellitus type 1 and type 2), estimated 10-year
individuals without New York Heart Association class
II–IV heart failure who were not receiving hemodialysis. ASCVD risk can also be used to guide the intensity of
statin therapy. For those with clinical ASCVD or with
In the RCTs reviewed, initiation of moderate-intensity
LDL-C (cid:2)190 mg/dL who are already in a statin benefit
therapy (lowering LDL-C by approximately 30%
to<50%)orhigh-intensitystatintherapy(loweringLDL-C group, it is not appropriate to estimate 10-year ASCVD
by approximately (cid:2)50%) is a critical factor in reducing risk. In primary prevention, additional factors may in-
fluence ASCVD risk in those for whom a risk-based
ASCVDevents.Moreover,statintherapyreducesASCVD
decision is unclear. These include a primary LDL-
events across the spectrum of baseline LDL-C
levels (cid:2)70 mg/dL. In addition, the relative reduction C (cid:2)160 mg/dL or other evidence of genetic hyperlip-
idemias, family history of premature ASCVD with
in ASCVD risk is consistent for primary and secondary
onset <55 years of age in a first-degree male relative
prevention and for various patient subgroups. Of note,
or<65yearsofageinafirst-degreefemalerelative,high-
theabsolutereductioninASCVDeventsisproportional
sensitivity C-reactive protein (cid:2)2 mg/L, coronary artery
to baseline absolute ASCVD risk. Therefore, statin
calcium score (cid:2)300 Agatston units or (cid:2)75th percentile
therapy is recommended for individuals at increased
for age, sex, and ethnicity (for additional information,
ASCVD risk who are most likely to experience a net
benefit in terms of the potential for ASCVD risk see http://www.mesa-nhlbi.org/CACReference.aspx.), ankle-
brachial index <0.9, and elevated lifetime risk of
reduction and the potential for adverse effects (Table 3;
ASCVD.
Figure 2).
The findings support the use of statins to prevent both
On the basis of this large and consistent body of evi-
dence, 4 major statin benefit groups were identified for nonfatal and fatal ASCVD events. Such an approach can
reduce the large burden of disability from nonfatal stroke
whom the ASCVD risk reduction clearly outweighs the
(for which women are at higher risk than men) and
risk of adverse events based on a strong body of evidence.
nonfatal CHD events. Primary and secondary prevention
These are 1) secondary prevention in individuals with
of ASCVD with statins can positively impact rising
clinicalASCVD,2)primarypreventioninindividualswith
primary elevations of LDL-C (cid:2)190 mg/dL, 3) primary healthcare costs. In addition, a high level of evidence was
foundthatstatinsreducetotalmortalityinindividualswith
prevention in individuals with diabetes 40 to 75 years of
a history of prior ASCVD events (e.g., secondary-
age who have LDL-C 70 to 189 mg/dL, and 4) primary
prevention settings). In individuals with no prior history
prevention in individuals without diabetes and with esti-
mated 10-year ASCVD risk (cid:2)7.5%, 40 to 75 years of age of ASCVD events (e.g., primary-prevention settings),
there is moderate evidence that statins reduce total mor-
who have LDL-C 70 to 189 mg/dL. Moderate evidence
talityinindividualsatincreasedASCVDrisk.Itshouldbe
supports the use of statins for primary prevention in in-
dividuals with 5% to <7.5% 10-year ASCVD risk, 40 to noted that 2 meta-analyses published after the completion
of the Expert Panel’s systematic review provide strong
75 years of age with LDL-C 70 to 189 mg/dL. Selected
individuals with <5% 10-year ASCVD risk, or <40 or evidence that statins reduce total mortality in primary
>75 years of age may also benefit from statin therapy. prevention (12,13).
Cliniciansandpatientsshouldengageinadiscussionofthe
potential for ASCVD risk-reduction benefits, adverse ef- 3. Critical Questions and Conclusions
fects, drug–drug interactions, and consider patient prefer-
ences for treatment. This discussion also provides the
3.1. Identification of CQs
opportunity to re-emphasize healthy-lifestyle habits and
address other risk factors. Although limited to 3 CQs, these questions were consid-
ClinicalASCVDisdefinedbytheinclusioncriteriafor ered the most important to answer in order to identify
the secondary-prevention statin RCTs (acute coronary whomtotreatandwithwhattreatment(s)and toconsider
syndromes, a history of MI, stable or unstable angina, how intensively the treatments should be used. The first 2
coronary or other arterial revascularization, stroke, tran- CQsevaluatedtheevidenceforLDL-Candnon–HDL-C
sient ischemic attack, or peripheral arterial disease pre- goalsforthesecondaryandprimarypreventionofASCVD
sumed to be of atherosclerotic origin). For primary with cholesterol-lowering drug therapy. Titration to spe-
prevention in individuals without clinical ASCVD or cific LDL-C goals has been considered a fundamental
diabetes who have an LDL-C 70 to 189 mg/dL, the therapeutic strategy in deciding on the adequacy of
estimated absolute 10-year risk of ASCVD (defined as cholesterol-lowering therapy for secondary and primary
nonfatal MI, CHD death, or nonfatal and fatal stroke) prevention. Therefore, a comprehensive systematic review
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2013ACC/AHABloodCholesterolGuideline July1,2014:2889–934
Heart-healthy lifestyle habits are the foundation of ASCVD prevention
(See 2013 AHA/ACC Lifestyle Management Guideline)
Age ≤75 y
High-intensity statin
Yes (Moderate-intensity statin if not
Age f≥o2r1 s yta atnind t ah ecraanpdyidate Yes CAlSinCiVcaDl candidate for high-intensity statin)
Age >75 y OR if not candidate for
Yes high-intensity statin
No Moderate-intensity statin
Definitions of High- and Moderate-
Intensity Statin Therapy*
(See Table 5)
High Moderate LDmL-gC/ d≥L190 Yes ca(MndoiddHeairtgeah tfe-o-irnin htteeignnhss-iiittnyyt essnttasatititniyn isf tnaotitn )
Daily dose lowers Daily dose lowers
LDL-C by approx. LDL-C by approx.
≥50% 30% to <50%
No
Regularly monitor adherence to
lifestyle and drug therapy with
lipid and safety assessments Yes Moderate-intensity statin
(See Fig 5) Diabetes
LDL-C 70-189 mg/dL
Age 40-75 y Yes EstimatHeidg 1h0-i-nyt eAnSsCitVyD s traistkin ≥7.5%†
No
DM age <40 Primary prevention
or >75 y or (No diabetes, LDL-C 70 to 189 mg/dL, and not receiving statin therapy)
LDL-C <70 Estimate 10-y ASCVD risk every 4-6 y
mg/dL using Pooled Cohort Equations†
10-yr< iAs5kS%‡CVD Aagned <mL4Dg0L/ do-CLr ‡ ><7159 0y (M10ion-dtyee nAr≥saS7itt.eCy5- V% sotDar thriniisg)kh- (M10o5-dy%e A rstaStoateC t<i-Vni7n)D.t5e %rnissikty
In selected individuals, additional
factors may be considered to inform
treatment decision making§
Emphasize adherence to lifestyle
Manage other risk factors
Clinician-Patient Discussion Monitor adherence
Prior to initiating statin therapy, discuss:
1. Potential for ASCVD risk-reduction benefits║ No to statin
2. Potential for adverse effects and drug–drug interactions¶
3. Heart-healthy lifestyle Yes to statin
4. Management of other risk factors
5. Patient preferences
6. If decision is unclear, consider primary LDL-C ≥160 mg/dL, family history of premature Encourage adherence to lifestyle
ASCVD, lifetime ASCVD risk, abnormal CAC score or ABI, or hs-CRP ≥2 mg/L§ Initiate statin at appropriate intensity
Manage other risk factors
Monitor adherence* (See Fig 5)
Figure2. SummaryofStatinInitiationRecommendationsfortheTreatmentofBloodCholesteroltoReduceASCVDRiskinAdults
(SeeFigures3,4,and5forMoreDetailedManagementInformation)
ColorscorrespondtotheClassesofRecommendationinTable1.AssessmentofthepotentialforbenefitandriskfromstatintherapyforASCVDpreventionprovidesthe
frameworkforclinicaldecisionmakingincorporatingpatientpreferences.
*PercentreductioninLDL-Ccanbeusedasanindicationofresponseandadherencetotherapy,butisnotinitselfatreatmentgoal.
yThePooledCohortEquationscanbeusedtoestimate10-yearASCVDriskinindividualswithandwithoutdiabetes.Theestimatorwithinthisapplicationshouldbeusedto
informdecisionmakinginprimarypreventionpatientsnotonastatin.
zConsidermoderate-intensitystatinasmoreappropriateinlow-riskindividuals.
xForthoseinwhomariskassessmentisuncertain,considerfactorssuchasprimaryLDL-C(cid:2)160mg/dLorotherevidenceofgenetichyperlipidemias,familyhistoryof
prematureASCVDwithonset<55yearsofageinafirst-degreemalerelativeor<65yearsofageinafirst-degreefemalerelative,hs-CRP(cid:2)2mg/L,CACscore(cid:2)300Agatston
units,or(cid:2)75thpercentileforage,sex,andethnicity(foradditionalinformation,seehttp://www.mesa-nhlbi.org/CACReference.aspx),ABI<0.9,orlifetimeriskofASCVD.
Additionalfactorsthatmayaidinindividualriskassessmentmaybeidentifiedinthefuture.
kPotentialASCVDrisk-reductionbenefits.TheabsolutereductioninASCVDeventsfrommoderate-orhigh-intensitystatintherapycanbeapproximatedbymultiplyingtheestimated
10-yearASCVDriskbytheanticipatedrelative-riskreductionfromtheintensityofstatininitiated(w30%formoderate-intensitystatinorw45%forhigh-intensitystatintherapy).
ThenetASCVDrisk-reductionbenefitisestimatedfromthenumberofpotentialASCVDeventspreventedwithastatin,comparedtothenumberofpotentialexcessadverseeffects.
{Potentialadverseeffects.Theexcessriskofdiabetesisthemainconsiderationinw0.1excesscasesper100individualstreatedwithamoderate-intensitystatinfor
1yearandw0.3excesscasesper100individualstreatedwithahigh-intensitystatinfor1year.InRCTs,bothstatin-treatedandplacebo-treatedparticipantsexperiencedthe
samerateofmusclesymptoms.Theactualrateofstatin-relatedmusclesymptomsintheclinicalpopulationisunclear.Musclesymptomsattributedtostatintherapyshould
beevaluated(seeTable8,SafetyRecommendation8).
ABIindicatesankle-brachialindex;ASCVD,atheroscleroticcardiovasculardisease;CAC,coronaryarterycalcium;hs-CRP,high-sensitivityC-reactiveprotein;LDL-C,low-density
lipoproteincholesterol;MI,myocardialinfarction;andRCT,randomizedcontrolledtrial.
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