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April,2010

Volume27,IssueNo.2

NewCanadianDyslipidemiaGuidelines
WhatsNewandHowDoesitAffectPractice?
Cardiovasculardisease(CVD)remainstheleadingcauseofdeathforCanadians;themostrecentdatashows CVDclaimed71,000Canadiansin2005,including3000Saskatchewanresidents1.OfallthecausesofCVD,coronary arterydisease(CAD)hasbeenfoundtobethemostcommon2.ThemostsignificantriskfactorfordevelopingCADis elevatedlowdensitylipoprotein(LDLC).TherearenumerousstrategiestoreduceLDLC,butoptimalapproachesin screeningandmanagingcomplexpatientshaveoftennotbeenimplemented.Inresponse,Canadianspecialistsand severalorganizationsreleasedthe2006DyslipidemiaGuidelinestoaidpractitionersinidentificationandtreatmentof patientsatriskforprimaryandsecondaryCVDevents3. Sincethecompletionofthe2006guidelines,severallandmarkstudieshavebroughtnewinformationand evidenceintopractice.Thecommitteereviewedallliteraturefocusedonthescreeningandtreatmentofdyslipidemia publishedbetweenJanuary1st,2006andFebruary1st,2009andonlyincludedblinded,randomizedstudiesthatfocused oncardiovascularoutcomes4.Theanalysisofliteraturehasenabledseveralkeyfeaturestobeincorporatedintothe 2009guidelines:newscreeningtoolsandmarkersareavailable,lipidtargetsaresimplified,andmorepatientspecific treatmentrecommendationsaresuggested.

Whathaschangedfromthe2006guidelines?

Screeningcriteria4,5
The2009guidelinesincludemoresharplydefinedguidelinesonwhoshouldhaveafastingplasmalipidprofile andbescreenedforCVDrisk.The2009guidelinesalsosuggestreassessmentofCVDriskevery35yearsinappropriate patients.Differencescomparedtothe2006guidelinesarenotedingreentext.
Whoshouldbe screenedwithafasting plasmalipidprofile? AllMen>40years AllWomen>50yearsorpostmenopausal Childrenofparentswithseverelipiddisorder(ie.,familialhypercholesterolemia,chylomicronemia) Adultsofanyagewhohaveoneormoreofthefollowingriskfactors: o Diabetesmellitus o Physicalsignsofhyperlipidemia(xanthelasma,xanthoma,etc.) o Currentsmokers(vs.currentsmokersandrecentlyquitinlastyear) o Hypertension o HIVtreatedwithhighlyactiveantiretroviraltherapy 2 o Obesity,increasedwaistcircumference,orBMI>27kg/m (vs.justwaistcircumference) o PrematureCADinfirstdegreerelative<60yearsofage(vs.<55men,<60women) 2 o Chronickidneydisease,eGFR<60mL/min/1.73m (vs.noeGFRdefined) o Autoimmunedisease(systemiclupus,psoriasis,rheumatoidarthritisvs.justlupusincluded) o Anyevidenceofatherosclerosis o Erectiledysfunction AdaptedfromPharmacistsLetter6

RiskAssessment
Thenewguidelineshavechangedrecommendationsforstratifyingpatientstohigh,moderateorlowrisk, especiallyinthemoderateriskcategory;lowriskstratificationremainsthesame.Newassessmenttoolsincludetheuse ofbothamodifiedFraminghamRiskScore(FRS)model(http://www.framinghamheartstudy.org/risk/gencardio.html) andaReynoldsRiskScore(RRS,http://www.reynoldsriskscore.org/Default.aspx)4.Framinghamhasbeenmodifiedto officiallyincludediabetes7.TheRRSusesthesamecriteriaofFRS,exceptitincludestheuseofhighsensitivityC reactiveprotein(hsCRP)andfamilyhistory,butisbasedonnondiabeticindividuals8. Thecombinationofthenewtoolsallowsfortheuseofmoremarkers,namelyhsCRPinmoderaterisk,to betterdefineapatientsriskofCVD.Creactiveprotein(CRP)isacomponentoftheimmunesystemwhichcauses inflammationandsubsequentimmunesystemactivity.CRPacutelyrisesintheeventoftraumaorillnessbutcannot reliablypredictanycardiovascularrisk.HsCRPhasthesamefunctionbutisalsoamarkerofchronicinflammationin thebody9.IndividualswithhighhsCRPhavechronicinflammation,whichleadstowhitebloodcellinvasionand damagetothearterialwalls,earlyinitiationofatheroscleroticplaqueswithinthearteries,andacuterupturingofthese plaques,increasingthelikelihoodofacardiovascularevent10,11.HowwellhsCRPcorrelatedwithCVDriskwaslargely speculativeuntiltheJUPITERtrialshowedtreatingpatientswithelevatedhsCRP,butnormalLDL,hadclinically significantbenefits12.Thus,hsCRPlevelscanhelpwiththedecisiontoinitiatetreatmentinmoderateriskindividuals, notedbelow.LevelsofhsCRPlevelscanbeelevatedbyacuteinflammatoryprocesses,infectionsandinjuries.13This shouldbetakenintoconsiderationwhenevaluatinginitialhighvaluesofhsCRP.13 CVDRiskStratificationfor20094 RiskLevel FRSScore RRSScore LDLC TC/HDLCRatio HsCRP HighRisk* >20% >20% NA NA NA ModerateRisk Men>50:>2mg/L 10%19% NA >3.5mmol/L >5.0 Women>60:>2mg/L LowRisk <10% NA NA NA NA
*PatientwithCAD,peripheralvasculardisease,atherolosclerosisandmostpatientswithdiabetesareautomaticallyhighrisk, regardlessofothermarkers Bold/Greenarenewrecommendationscomparedtothe2006guidelines

InitiatingTreatmentandTargetLevels Thedecisiontoinitiatetreatmentinmoderateriskpatientswithborderlinelipids(LDLC>3.5mmol/Land
TC/HDLC>5)wasoftenadifficultchoice.The2009guidelinesintroduceusinghsCRPandfamilyhistoryasamarkerfor initiatingtreatmentinmoderateriskpatientstohelpmakethedecisioneasier4. Anotherimportantchangeistheprimaryandsecondarytargetgoals.ThepreviousguidelinesfocusedonLDLC <2mmol/LasaprimarytargetandtheTC/HDLratioof<4.0asasecondarytarget;thenewguidelinesnowdefinea primarytargetasLDLC<2mmol/L,a50%decreaseormoreofLDLC,orapoB<0.8g/L4,5.Goingfora50%decreaseor moreofLDLCmaybeamoreaggressiveapproachthansomecliniciansareaccustomedto.Itshouldbenoted, however,thatseveralofthelandmarklipidtrials(4S,CARE,HPS,CARD,ASCOT)whichhadstrongoutcomedateon reductionofMIanddeathreducedLDLbyonly1835percent.13.Also,thereisnooutcomeevidencetosupportthe additionofaseconddrugtoapatientsmedicationregimentoachievethenewtargets.13 ApoBisaprimaryapolipoproteinaproteinresponsibleforcarryingcholesteroltotissuesforLDLC.The higherapatientsapoB,themoreLDLCistransferredtotissues,andanincreaseinplaqueformationandCVDrisk results15.TheinclusionofapoBintheguidelinesmoreclearlyidentifiesitsroleindyslipidemiaasaprimarytreatment target,assomestudieshavefoundapoBisabetterpredictorofCVDthanLDLC,thoughtreatmentisthesame

regardlessofthetreatmentparameter14.Theaimofthesenewprimarytargetsistokeeprealisticgoalswhilestill maximizingbenefits4.

TreatmentInitiationandPrimaryTargetsfor20094,5
RiskLevel
HighRisk

WhentoInitiateTreatment
Allpatients,immediately

PrimaryTargetLevels
LDLC<2mmol/L Or >50%decreaseinLDLCorapoB<0.8g/L LDLC<2mmol/L Or >50%decreaseinLDLCorapoB<0.8g/L *Thebenefitsofthistargetinmoderate riskislessclear;guidelinessuggestusing clinicaljudgmenttodecideiftargetsare appropriate >50%decreaseinLDLC

GradeofRecommendation andLevelofEvidence
GradeI,LevelA

ModerateRisk

LDLC>3.5mmol/L TC/HDLC>5.0 HsCRP>2mg/Linmen>50orwomen>60 Iffamilyhistoryincreasesriskaccordingto RRS

GradeIIa,LevelA

LowRisk

LDLC>5mmol/L TC/HDLC>6withhightriglycerides

GradeIIa,LevelA

*Bold/greenindicatenewordifferentrecommendationscomparedtothe2006guidelines

TherearealsonewsecondarytargetsthatcanbepursuedinsteadofjusttheTC/HDLratio4.

SecondaryTargetsforCVDRiskReductionfor2009
SecondaryTreatmentGoals ConsiderthesetargetsafterachievingtargetLDLCorapoB: TC/HDLCratio<4 NonHDLcholesterol<3.5mmol/L apoB/apoA1ratio<0.8 Triglycerides<1.7mmol/L hsCRP<2mg/L *Clinicalbenefitsofachievingthesetargetsareunknown AdaptedfromPharmacistsLetter6

TreatmentRecommendations4,5,6
Themajordifferencesintreatmentrecommendationsareaimedathelpingachievesecondarytargetsthroughmore specificmedicationindicationsandlifestylechanges.Thesamebatteryofmedications,anddoses,arerecommendedin thenewguidelines.

LifestyleChanges
Theusualrecommendationsofsmokingcessationandeatinghealthyremain.However,insteadof suggesting150200minutesofexerciseperweektopatients,thenewguidelinessuggest3060minutesof moderateintensityexerciseperday.Stressmanagement,alowerBMIgoal(<25insteadof<27),andareductionof alcoholconsumption(onedrinkperdayforwomen,twoperdayformenpermitted)arealsoincludedinthenew guidelines.Finally,omega3supplementation(asopposedtospecificallysalmonoil)isrecommendedinthosewith elevatedtriglycerides.

AchievingPrimaryandSecondaryTargets
Majorchangesincludenew,detailedsuggestionsforlowertriglycerides,raisingHDLCandthe inclusionofhsCRPasanofficialtreatmenttarget.

TreatmentstoachieveTargets Target
LDLC LifestyleplusStatin

FirstlineMedication

SecondlineMedication
Add: bileacidsequesterant;or cholesterolabsorptioninhibitor;or Niacin(Niaspanorgenericcrystalline flushfreeniacinineffective) N/A

HDLC

Lifestyle:smokingcessation,weightloss(BMI<25),exercise(3060 min/d),moderatealcoholintake Niacinorfibrate*(lesseffective),plusstatin(forLDLC). Triglycerides Lifestyle:exercise(3060min/d),weightloss(BMI<25),restrict N/A refinedcarbohyydrates,reducealcoholintake,increaseomega3 fattyacids Triglycerides>10mmol/L: Fibrate*(toreducepancreatitisrisk) Triglycerides5mmol/Lto10mmol/L: Fibrate*oromega3fattyacid Triglycerides2to5mmol/Lonstatin,andhighrisk: Addfibrate*orniacin (unclearimpactonCADriskifLDLCisattarget) hsCRP Statin N/A *Fenofibraterecommendedincombinationwithstatintherapy;lessriskofmyotoxicitycomparedtogemfibrozil

MonitoringRecommendations4,6
Previousguidelinesdidnothavedetailsonmonitoringtreatment;thenewguidelinesnowhaveofficial monitoringparameters.
Baseline:Fastinglipidpanel,glucose,TSH(ashypothyroidismcontributestohyperlipidemia),liverfunction, creatinine,creatinekinase,apoBandapoA1(iftargetingastreatmentgoals) Followupmeasurements:Repeatliverfunctiontestsandcreatinekinaseeverysixto12months,withany changeinlipidtherapy,andintheeventofsymptoms. Niacin:ALTatbaselineandoneandthreemonthsafterstartingniacin;fastingglucoseandA1Ceverysixto12 months;uricacid Fibrates:Mayincreaseserumcreatinine;startwithlowestdoseandincreaseafterfollowupmeasurementsof creatinineandlipids. AdaptedfromPharmacistsLetter6

MonitoringSafety

WhatDoesitAllMean?
Theultimatequestionwiththenewguidelinesis,willitchangehowIpractice?Theshortanswerisno.Much ofwhatisnowrecommendediswhatclinicianshavebeendoingforsometime;theonlydifferenceisthenewbodyof evidencethataffirmswhateveryonehasbeendoing.

Thedifferencesinscreeningcriteriawillpreventhighriskpatientsfromslippingundertheradar,suchas thosewithrheumatoidarthritiswhomaynothavebeenscreenedinthepast.TheadditionoftheReynoldsRiskScore willalsohelpcliniciansprovidemoreaccurateriskassessmentforthosepotentiallyinthemoderateriskcategory,or ensurevalidityofaFraminghamRiskAssessment.Moderateriskpatientsarenowmoreeasilyidentifiedwiththe inclusionofhsCRPasamonitoringtool. TheadditionoftreatingelevatedhsCRPmayalsomeanpatientswhowouldnormallybeleftuntreatedwill nowreceivepotentiallybeneficialtherapy.TheJUPITERtrialfoundthattreatingpatients(rosuvastatinstudied)with elevatedhsCRP,butnormallipidlevels,significantlyreducedprimaryoutcomeevents(MI,stroke,arterial revascularization,hospitalizationforunstableanginaordeathfromCVcauses).TheNNTreportedwas31over4years9. TheNNTfor1.9years,theactuallengthofthestudy,worksoutto82whichisquitesimilartotheresultsofotherstatin drugtrials.13 ApoBhasalsobeenincludedasaprimarytreatmenttarget,butwhetherlaboratoriesorclinicianswilladoptit asaprimarytargethasyettobeseen.SomestudieshavefoundapoBpredictscoronaryeventriskbetterthanLDLC10; however,sincetherearenospecifictreatmentrecommendationstolowerapoBthatdifferfromtraditionaltreatment, treatmentwillremainthesameevenifaclinicianistargetingapoBastheprimarytreatmentparameter. Regardingtreatment,therearenotmanydifferencesinthenewguidelinesthatwillalterpractice.Themain changeisthesuggestiontotargetaLDLCdecreaseofgreaterthan50%,whichmaybemoreaggressivetreatmentthan someclinicianshaveimplemented.Thedrugtreatmentrecommendationsarewhathasbeenpracticedforsometime, suchasusingniacintofurtherlowerLDLCorraiseHDLandusingfibratestolowertriglycerides.Thenewguidelines provideaspecificplaceintherapyforthesetreatments,whereasbeforetheywerejustgeneralrecommendations. Thenewguidelineshelpprovidecontinuityintreatmentbetweenclinicians,openuptreatmenttonewpatients, andmakestratifyingriskmorereliableandaccurate.Concernsregardingthenewguidelinesincludea)thepotentialto increasethenumberofpatientsusingasecondlipidmodifyingdrugwithoutoutcomedatatoverifybenefitand b)withmorelowerriskpeoplequalifyingfortherapy,thepotentialforverylongtermtreatment(againwithsome uncertaintyregardingtherelativebenefitsandrisks). PreparedbyTerryDamm,SPEPstudent.EditedbyK.Jensen(SDIS)andL.Regier(RxFiles) References 1. StatisticsCanada.Mortality:SummaryListofCauses[Online].[2005Jan1;cited2010Feb26].Availablefrom: http://www.statcan.gc.ca/pub/84f0209x/84f0209x2005000eng.pdf. 2. CanadianInstituteofHealthResearch.InvestinginCanadasFuture[Online].[2006Nov13;cited2010Feb26]. Availablefrom:http://www.cihrirsc.gc.ca/e/24939.html. 3. Lau,D.,Gupta,M.,PearsonG.,etal.NewCanadianGuidelinesfortheDiagnosisandManagementofDyslipidemia, 2009Update[Online].TheMedicalPostEducationalSupplement.[2010Feb9;cited2010Mar8].Availablefrom: http://www.canadianhealthcarenetwork.ca/files/2010/02/Dyslipidemia_Guidelines_Feb2010.pdf

4. GenestJ,McPhersonR,FrohlichJ,etal.2009CanadianCardiovascularSociety/Canadianguidelinesforthediagnosis andtreatmentofdyslipidemiaandpreventionofcardiovasculardiseaseintheadult2009recommendations.CanJ Cardiol2009;25:56779. 5. GenestJ,McPhersonR,FrohlichJ,etal.CanadianCardiovascularSocietypositionstatementrecommendationsfor thediagnosisandtreatmentofdyslipidemiaandpreventionofcardiovasculardisease.CanJCardiol2006;22:913 27. 6. CanadianCardiovascularSocietydyslipidemiarecommendations.PharmacistsLetter/PrescribersLetter 2009;25(11):251123. 7. DAgostino,R.,VasanR.,PencinaM.,etal.FraminghamsRiskScore.[cited2010Mar8].Availablefrom: http://www.framinghamheartstudy.org/risk/gencardio.html 8. RidkerP.,BuringJ.,RifaiN,CookN.Developmentandvalidationofimprovedalgorithmsfortheassessmentof globalcardiovascularriskinwomen:TheReynoldsRiskScore.JAMA2007;297:611619Availablefrom: http://www.reynoldsriskscore.org/ 9. Ridker,P.CReactiveProtein:ASimpleTesttoHelpPredictRiskofHeartAttackandStroke.Circulation.2003; 108:e8185e 10. BlumenthalS.,Campbell,C.JUPITER:UsinghsCRPtoidentifyprimarypreventionpatientswhomaybenefitfrom statintherapy.AccessedMarch15,2010.http://www.endocrinetoday.com/view.aspx?rid=32617 11.LloydJonesD.,LiuK.,TianL.NarrativeReview:AssessmentofCReactiveProteininRiskPredictionfor CardiovascularDisease.AnnalsofInternalMedicineJuly4,2006vol.145no.13542. 12.Ridger,P.,Danielson,E.,Fonseca,F.,etal.RosuvastatintoPreventVascularEventsinMenandWomenwith ElevatedCReactiveProtein:TheJUPITERtrial.NEnglJMed2008359:21952207 13.JensenB,RegierL.JupiterTrialOverview.[2008Nov;cited2010Apr5].Availableatwww.rxfiles.ca. 14.McQueenMJ,HawkenS,WangX,etal.(July2008)."Lipids,lipoproteins,andapolipoproteinsasriskmarkersof myocardialinfarctionin52countries(theINTERHEARTstudy):acasecontrolstudy".Lancet372(9634):22433. 14.Vaverkova,H.,KarasekD.,NovotnyD.,etal.ApolipoproteinBversusLDLcholesterol:Associationwithother riskfactorsforatherosclerosis.ClinBiochem.2009;42(12):124651.