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TheValueofPCSK9Inhibitors:AMatterofPerspective
DavidHuggar,PharmDMastersofPharmacotherapyCandidate
TheUniversityofTexasatAustinCollegeofPharmacyPharmacotherapyEducationandResearchCenter
UniversityofTexasHealthScienceCenteratSanAntonio
LearningObjectives1. Summarizetheepidemiologyandpathophysiologyofatheroscleroticcardiovascular
disease(ASCVD)2. SummarizerecommendationsforpreventionofASCVD3. ReviewthePCSK9inhibitordrugclass,includingrelevantclinicalandeconomicanalyses4. IdentifyappropriatepatientpopulationforPCSK9inhibitoruse
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CardiovascularDisease&Hyperlipidemia
1. AtheroscleroticCardiovasculardisease(ASCVD)a. AmericanCollegeofCardiology/AmericanHeartAssociation(ACC/AHA)definitionsinclude1,2:
i. Myocardialinfarction(MI)ii. Coronaryheartdisease(CHD)iii. Unstableangina
b. OveralldeathrateattributabletoASCVD3
i. 230deaths/100,000Americansperyearii. Morethan2,150AmericansdieofASCVDeachday;1deathevery40secondsiii. 34%ofASCVD-associateddeathsoccurbeforeageof75years
c. CostsofASCVD3,4
i. EstimatedannualcostsforASCVD(2011)—$320.1billionii. Projectedtoincreasetomorethan$818billionannuallyby2030iii. Averagehospitalcharge(in2012)
1. Cardiac/vascularsurgery—$78,8972. Cardiacrevascularization—$149,4803. Percutaneousintervention—$70,027
Table1:RiskfactorsofASCVD2Modifiable Non-Modifiable
Smoker AgeObesity(BMI>30kg/m2) FamilyhistoryofearlyCVDHypertension MalesexDiabetesmellitus Race(AfricanorAsianorigin)Hyperlipidemia
2. Hyperlipidemia(HLD)a. Cholesterolisanessentialcomponentoflife5
i. Buildingblockofcellmembranesii. Componentofsteroidhormonesynthesisiii. Requiredforproductionofbileacids
b. RoleinASCVD6
i. Circulatingcholesterolpenetratesandaccumulatesinarterialwalls1. Initiatesinflammatoryresponse2. Enhancesfoamcell/plaqueformationleadingtopartialorcompleteocclusion
ii. AtherosclerosisincreasesriskofCHD,stroke,andperipheralvasculardiseasec. Lipidstransportedthroughoutbodyascomplexeswithproteins5,6
i. Low-densitylipoproteins(LDL)1. ElevatedlevelsareassociatedwithincreasedriskofCVD2. TakenupbyliverviamembraneLDL-receptors3. LDLparticlesizeinfluencesatherogenicpotential
ii. High-densitylipoproteins(HDL)1. Removescholesterolfromperipheraltissueandtransportstoliverforexcretion2. LowserumconcentrationsassociatedwithincreasedriskofCVDevents
iii. Triglycerides(TGs)1. Serumlevelsstronglyinfluencedbyrecentdietaryintake2. UnclearroleinASCVDdevelopment
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Fig.1—Cholesterolsynthesispathways
EncyclopediaBritannica.www.britannica.com/science/cholesterol.2007.
Hyperlipidemia(HLD)continuedd. FamilialHypercholesterolemia(FH)7-12
i. Geneticdefectsthatresultinhypercholesterolemia1. Autosomaldominantinheritancepattern2. MostmutationsoccurintheLDL-receptorgene—onchromosome193. MutationstoApolipoproteinB(ApoB)accountfor~5%ofFHcases4. Mutationstoproproteinconvertasesubtilisintype-9(PCSK9)accountfor~1%ofFHcases
ii. HeterozygousFH(HeFH)1. AssociatedwithLDLlevels250-350mg/dL2. ~1:500peopleglobally;500,000-1,300,000casesinUS3. SevereHeFHassociatedwithsignificantlyincreasedriskofCVD
iii. HomozygousFH(HoFH)1. AssociatedwithLDLlevels>500mg/dL2. ~1:1,000,000peopleglobally;300-500diagnosedcasesinUS3. Highlevelsofplasmacholesteroloftenprevalentatbirth4. UntreatedpatientsoftenexperiencefirstmajorCVeventduringadolescence
iv. Clinicalpresentation1. Strongfamilyhistoryofelevatedcholesterollevelsorearlycardiovascularevents2. Cholesterollevelsresistanttotreatmentinparent(s)3. Xanthomas—cholesteroldepositsinskinortendons4. Xanthelasmas—cholesteroldepositsintheeyelids5. Elevatedlevelsofinflammatorymarkersreflectearlyatherogenesis6. CoronarycalcificationsignificantlymoreprominentinadolescentswithFH
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Hyperlipidemia(HLD)continuede. SupplementalpredictorsofCVrisk6,14-16
i. Apolipoprotein-B(ApoB)1. Primaryproteincomponent
ofnon-HDL2. Necessaryforlipidtransport
andLDLuptake3. Elevatedlevelsassociated
withincreasedriskofASCVDii. High-sensitivityC-reactiveprotein(hs-CRP)
1. Acutephasereactantusedtomeasureinflammation
2. ElevatedlevelsconsideredpredictiveoffutureCVDeventrisk
iii. Lipoprotein(a)1. Lipoprotein(a)transportslipidsand
reducesfibrinolysis2. Hasstructuralsimilaritiestoplasminogen3. Levelsaregeneticallydeterminedandremainrelativelyconstant
iv. Lipoprotein-associatedphospholipaseA21. Aninflammatoryenzymeassociatedwithatherosclerosis2. ElevatedlevelsshowntodoubleriskofCVevents3. Higherpredictivevaluewhenelevatedinconcertwithhs-CRP
v. Coronarycalciumscore1. Calciumdepositsinarterialwallsasresponsetoinflammation2. Calcificationstiffensarterialwallsandreduceselasticity3. SignificantlymoreprominentinadolescentswithFHthanthosewithout
Fig.3—TreatmentoptionsforHLD
Statins
•Atorvastatin•Fluvastatin•Lovastatin•Pravastatin•Rosuvastatin•Simvastatin
Niemann-PickInhibitor
•Ezetimibe
PCSK9Inhibitors
• Alirocumab• Evolocumab
FibricAcids
•Fenofibrate•Gemfibrozil
Fig.2—AHAFHDiagnosis13
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TreatmentGuidelines
Fig.4—AmericanCollegeofCardiology/AmericanHeartAssociationguidelinesfortheuseofstatintherapyinat-riskpatients17
Fig.5—NationalLipidAssociationguidelinesformanagementofhyperlipidemia2
3. Controversiessurroundinglipidgoalsa. ACC/AHA—treatment-drivenguidelines18,19
i. 4S—simvastatinreducesall-causemortalityinpatientswithpriorMIandhyperlipidemiaii. WOSCOPS—pravastatinreducedincidenceofMIanddeathinpatientswithmoderate
hyperlipidemiaandnohistoryofCVDb. NLA—LDLgoal-drivenguidelines20
i. PROVEIT-TIMI22—HigherdosestatinresultedinLDL<70mg/dLandbetteroutcomesc. Dearthofstudiescomparingtreatmentandgoal-drivenapproaches
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LDLGoal-DrivenTherapy
MurphySA,CannonCP,BlazingMA,etal.Reductionintotalcardiovasculareventswithezetimibe/simvastatinpost-acutecoronarysyndrome:TheIMPROVE-ITtrial.JAmColl
Cardiol.2016;67(4):353-61.Objective • ToidentifywhetheradditionalLDL-loweringaddingezetimibetostatintherapyis
clinicallybeneficialDesign • Multicenter,double-blind,randomizedcontrolledtrial
• n=18,144• Medianfollow-up:6years
InclusionCriteria
• Age≥50years• RecenthospitalizationforACS• LDL-C≥50mg/dL
ExclusionCriteria
• StrokeorTIA• Useofstatinmorepotentthansimvastatin40mg• UntreatedLDL≥125mg/dL,treatedLDL≥100mg/dL• PlannedCABGforACSevent
PrimaryOutcome
• Compositeof:CVmortality,majorCVevent,ornonfatalstroke
Interventions • Simvastatin40mg+ezetimibe10mgdaily,or• Simvastatin40mg+placebodaily
Results Primaryoutcome:• CompositeofCVmortality,majorCVevent,ornonfatalstroke:32.7%vs.34.7%[HR0.94;CI0.89-0.99;p=0.016]
Secondaryoutcomes:• Compositeofall-causemortality,majorCVevent,ornonfatalstroke:38.7%vs.40.3%[HR0.95;CI0.9-1.0;p=0.03]
• CompositeofCVmortality,nonfatalMI,urgentrevascularization:17.5%vs.18.9%[HR0.91;CI0.85-0.98;p=0.02]
• All-causemortality:15.3%vs.15.4%[HR0.99;CI0.91-1.07;p=0.78]• MortalityfromCVcauses,MI,orstroke:20.4%vs.22.2%[HR0.9;CI0.84-0.96;p=0.003]• Stroke:4.2%vs.4.8%[HR0.86;CI0.73-1.0;p=0.05]• MI:13.1%vs.14.8%[HR0.87;CI0.8-0.95;p=0.002]• LDLat1-yearfollow-up:53.2vs.69.9mg/dL(p<0.001)
Safety • Nodifferenceinpre-specifiedsafetyendpointsAuthor’sConclusion(s)
• Lipid-loweringtherapywithezetimibeplussimvastatinimprovedclinicaloutcomes,supportingintensivelipid-loweringtherapyafteraninitialCVevent.
ReviewerCritique
• Useofmoderate-intensitystatininhigh-riskpopulationisnotstandardofcare• LowerserumLDLassociatedwithsignificantdecreasesinMI,stroke,andCV-relatedmortality
• Establishesaroleforadditionofnon-statintherapyinhigh-riskpatients
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ProproteinConvertaseSubtilisin/KexinType-9(PCSK9)
4. PhysiologicfunctionofPCSK922a. DegradeshepaticLDLreceptorsb. FewerLDLreceptorsresultsinhigherserumLDLconcentrationsc. Sterolreceptorelementbindingproteins(SREBP-2s)regulatePCSK9andLDL-receptorproductiond. StatinsinduceproductionofPCSK9e. PCSK9functioncanbeinhibitedwithmonoclonalantibodies(mAbs)
i. Bindtheepidermalgrowthfactor-likeA(EGF-A)domainii. EGF-AisthecatalyticdomainwherePCSK9bindsandinitiatesLDL-Rdegradation
Fig.6—TheroleofPCSK9inlipidmetabolism
5. PCSK9roleinCVD
a. Gain-of-function(GOF)mutationstoPCSK9promoteLDL-receptordegradationandresultinhighserumLDLconcentrations,earlystrokeandMI22,23
i. ThreegenerationsofFrenchfamilywithGOFmutationhadserumLDLconcentrationsof466mg/dLb. Loss-of-function(LOF)mutationstoPCSK9inhibitLDL-receptorbreakdownandresultinlowserumLDL
concentrations22,24i. TwowomenwithLOFmutationsresultedinserumLDLconcentrationsmeasured~15mg/dLii. IncreasedratesofLOFmutationsinblacksfoundtoresultin28%lowerserumLDLconcentrations
andnearly90%lowerriskofCAD6. PCSK9Inhibitors25,26
a. Alirocumab(Praluent®)[Regeneron/Sanofi]—fullyhumanmAbapprovedJuly24th,2015i. 75mg,150mgsqinjectionevery2weeksii. AWP~$14,600/year
b. Evolocumab(Repatha™)[Amgen]—fullyhumanmAbapprovedAugust27th,2015i. 140mgsqinjectionevery2weeks,or420mgsqinjectionevery4weeksii. AWP~$14,100/year
c. Investigationali. RN316(bococizumab)[Pfizer]—humanizedmAbii. LY3015014[EliLilly]—fullyhumanmAb
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Fig.7—TimelineofPCSK9inhibitordiscoveryanddevelopment
GearingME.Apotentialnewweaponagainstheartdisease:PCSK9inhibitors.HarvardUniversity.2015.
7. Currentlitigationa. AmgencontendsRegeneron/Sanofiinfringedonevolocumabpatentsb. Regeneron/Sanofiarguethepatentswereinvalidc. UScourtsruledinfavorofAmgeninMarchd. Praluent™maybetakenoffthemarket
8. FDAapprovedindications25,26a. AdditionalloweringofLDLinpatientsunabletocontrolserumlevelswithcurrenttreatmentoptionsb. Asanadjuncttodietandmaximally-toleratedstatintherapyinselectpatientgroups
Table3:FDAapprovedindicationsforPCSK9inhibitorsDrug Adjunctive
therapyforHeFH
AdjunctivetherapyforHoFH
Adjunctivetherapyinpatientsw/clinicalASCVDrequiringadditionalLDL-lowering
Alirocumab √ √Evolocumab √ √ √
9. Safety25-27
a. Adverseeffects:i. Diarrhea,increasedserumtransaminases,injection-sitereactions,hypersensitivityreactions,
infection,myalgiaii. Neurocognitiveimpairment
1. 2ndmostcommonpatient-reportedadverseeffectofstatins2. Mechanismofdevelopmentisunclear,orevenrelatedtocholesterollevels
a. Decreasedratesofneuronalre-myelinationduetodecreasedcholesterolb. Decreasedcholesteroldeliverytoneuronscausingimpairedsynapticfiring
3. FDAhasmandatedfurtherassessmentinphaseIVstudies
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PreliminaryOutcomes
Title ODYSSEYLONGTERM27 OSLER28
OSLER-1 OSLER-2Objective • Toobtainlonger-termdataon
alirocumab’ssafetyandLDLcholesterolreduction
• Toobtainlonger-termdataonevolocumab’ssafety,side-effectprofile,andLDLcholesterolreduction
Design • Multicenter,double-blind,parallel-group,randomized,controlledtrial
• n=2,310• ITTanalysis
• Twoopen-label,randomized,controlledtrialso OSLER-1:PhaseIIo OSLER-2:PhaseIII
• Eachtrialcomposedof5-7smallertrials• n=4,465
InclusionCriteria • ≥18years• Highriskforcardiovascularevent:
o HeFHo CHDorriskequivalent
• LDL-C≥70mg/dL• Receivinghigh-dosestatintherapyormaxtolerated≥4weeks
• 18-80years• Highriskofcardiovascularevent• LDL75-189mg/dL• Stableonstatintherapy≥4weeks
ExclusionCriteria • LDL<70mg/dLorTG>400mg/dL• Recentorfutureplasmaexchange• ACS,stroke,orPVDinterventioninprevious3mos.
• NYHAclassIIIorIV• HoFH
• ClinicaldiagnosisofHoFH• Lipoproteinapheresisinpreceding4months• Malignancy• RecentMIorstroke• 10-YearFraminghamriskscore>10%
Interventions • Statin+alirocumab150mgsqQ2W• Statin+placebosqQ2W• Randomized2:1
• Standardtherapy+evolocumabo Evolocumab140mgQ2W,oro Evolocumab420mgQ4W
• Standardtherapy+placebo• Randomized2:1
MeanAge 60.4vs.60.6years 57.8vs.58.2yearsHxofCHD 68%vs.70% 19.8%vs.20.6%MedianTClevel 153vs.152mg/dL 202vs.205mg/dL
MedianLDLlevel 123vs.122mg/dL 120vs.121mg/dLPrimaryOutcomes • ChangeinLDL-Cfrombaselinetoweek24:
-74.2vs.-3.6mg/dL(p<0.001)• Incidenceofadverseevents:69.2%vs.64.8%(p=NR)
SecondaryOutcomes
• LDL-C<70mg/dL:79.3%vs.8.0%(p<0.001)• LDL-CΔfrombaseline-week78:-52.4mg/dLvs.+3.6mg/dL(p<0.001)
• Post-hocmajorCVevents:1.7%vs.3.3%(p=0.02)
• NonfatalMI:0.9%vs.2.3%(p=0.01)
• %changeinLDL-Cfrombaseline:61%(CI59-63%,p<0.001)
• LDL<70mg/dLat12weeks:73.6%vs.3.8%• Cardiovasculareventrates:0.95%vs.2.18%[HR0.47,CI0.28-0.78(p=0.003)]
AnyAE 81%vs82.5%(p=0.4) 69.2%vs.64.8%(p=NR)SeriousAE 18.7%vs.19.5%(p=0.66) 7.5%vs.7.5%(p=NR)Myalgia 5.4%vs.2.9%(p=0.006) 6.4%vs.6.0%(p=NR)NeurocognitiveAE 1.2%vs.0.5%(p=0.17) 0.9%vs.0.3%(p=NR)
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Pharmacoeconomics
10. Sowhat?30-32a. Americansspent~$310billiononallmedicationsin2015
i. $18.7billionspentoncholesterol-loweringmedicationsb. PCSK9inhibitorsprojectedtobethecostliestdrugclassever
i. Estimated$16B-$150billionadditionalspendannuallyintheUSc. Anestimated3in5bankruptciesareduetomedicalbillsd. Hospitalandhealth-systempharmaciestraditionallyviewedascost-centers
11. ACC/AHAeconomicanalysis33a. Publishedformalrecommendationsforinclusionofcostinassessingthevalueofcareb. Valueisdefinedasafunctionofresults(eg.safety,outcomes)andcostc. Summaryofimplementationrecommendations
i. Analysesshouldbeundertakenfromthesocietalperspectiveii. AnalysesshouldbelimitedtouseofdatarelevanttotheUnitedStatesorNorthAmericaiii. Thresholdsforvalueshouldincludeanupperandlowerboundaryiv. Performancemeasuresshouldconsidercostanalysesresults
12. Pharmacoeconomicanalysis34-38a. Subsetofoutcomesresearchintendedtoprovideobjectivemeasuresofvalueb. Valueisassumedfromtheperspectiveofeithersociety,payers,providers,orpatientsc. Fourbasictypesofanalysescomparecostsinputsofaproduct/servicewithoutcomes
Table3:PharmacoeconomicanalysesMethodology CostMeasurementUnit OutcomeMeasurementUnit
Cost-minimizationanalysis $orothermonetaryunit N/A;assumedequivalentCost-benefitanalysis $orothermonetaryunit $orothermonetaryunitCost-effectivenessanalysis $orothermonetaryunit AcommonnaturalunitCost-utilityanalysis $orothermonetaryunit Quality-adjustedlifeyear(QALY)or
otherutilityAnalysesshouldemployoneof:societal,payer,provider,orpatientperspective
Adaptedfrom:RascatiKL.Essentialsofpharmacoeconomics.2nded.Baltimore,MD.LippincottWilliams&Wilkins.2014.
d. Cost-effectivenessanalysis(CEA)i. Comparesrelativecostsandoutcomesof≥2products/servicesii. Cannotcompareproducts/serviceswithdifferentoutcomemeasuresiii. Doesnotaccountfordifferencesinside-effectprofiles
e. Cost-utilityanalysis(CUA)i. Comparesrelativecostsandutility-weightedoutcomesof≥2products/servicesii. Utilityweightsarea0.0(death)to1.0(perfecthealth)measureofoutcomepreferenceiii. Incorporatespatientorsocietalpreferencesintovaluemeasures
f. Measuringvaluei. Willingness-to-pay(WTP):Howmuchpeoplearewillingtopaytoreducethechanceofanadverse
healthoutcomeii. Incrementalcost-effectratio(ICER):(CostA–CostB)/(OutcomeA–OutcomeB)iii. Quality-adjustedlifeyears(QALYs):Outcomesinyearsoflifegained,adjustedforpatientpreferenceiv. Budgetaryimpact:theestimatedoverallcostofaddingaproducttotheformulary
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Pharmacoeconomicanalysiscontinued34-38
g. Historicvaluebenchmarksi. Regularlycited$50,000/QALYthresholdstemsfromacongressionalmandatethatdialysisbe
coveredforMedicarerecipientsii. TheWorldHealthOrganization(WHO)valuesQALYsat3xGDPpercapita
h. Recentvaluebenchmarksi. NewtreatmentoptionsforhepatitisCwereevaluatedashigh-to-reasonablevalueat
≤$20,000/QALYii. Meta-analysesofcurrentdialysisvaluereportsICERsbetween$65,496-$488,360perQALY
EconomicLiterature
TiceJA,OllendorfDA,CunninghamC,PearsonSD,KaziDS,etal.PCSK9inhibitorsfortreatmentofhighcholesterol:effectiveness,valueandvaluebasedpricebenchmarks.ICERNovember2015.
Purpose • ToevaluatethecomparativeclinicaleffectivenessandcomparativevalueofPCSK9inhibitorsasaclassforpatientswithelevatedLDL
Design • Cost-utilityanalysiso Carevalueo Budgetaryimpact
ScenariosModeled
• Familialhypercholesterolemia(FH)• ClinicalCVD—secondaryprevention
o Statin-intolerant(assumed10%)o Statin-tolerant,notatLDLgoal(<70mg/dL)
• Willingness-to-paythresholdso $50,000/QALYo $100,000/QALYo $150,000/QALY
PopulationsModeled
Outcomes • Costperquality-adjustedlife-year(QALY)Methods • UsedCVDpolicymodel
o EntireUSadultpopulationage35-74yearsin2015o Assumedhealthsystemperspectiveforbothanalyses
• Definedfamilialhypercholesterolemiaas:o LDL>250mg/dLwithoutstatinuseo LDL≥200mg/dLwithstatinuse
• Stratified10%ofthepopulationwithhistoryofCVDtomodelstatin-intolerance• Appliedlifetimehorizonof95-yearsold• Discountedfuturecostsandbenefitsby3%eachsuccessiveyear
Assumptions • Costsfromthehealthsystemperspective• DrugeffectsonoutcomesaredirectlyproportionaltodegreeofLDLreduction
Abletotoleratestatin?
Yes-Treatmentwithstatinalone-Treatmentwithstatinplusezetimibe-TreatmentwithastatinplusPCSK9inhibitor
No-Notreatment-Treatmentwithezetimibealone-TreatmentwithaPCSK9inhibitor
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• PCSK9inhibitorshavenoeffectonriskofstroke• Tenpercentofpersonsexposedtostatinsareintolerant• Ageandsexspecificcostswereextrapolatedfromnationaldata• Annualcostbasedonwholesaleacquisitioncost
o Ezetimibe—$2,828/yro PCSK9inhibitors(class)—$14,350/yr
• ~2.6millionpersonswouldreceiveaPCSK9inhibitorinthefollowing5years• Budgetimpactthresholdis$904million
Results Value-basedpricebenchmarksforPCSK9inhibitortherapy
Population CareValuePrice:$100K/QALY
CareValuePrice:$150K/QALY
MaxPriceatPotentialBudgetImpactThreshold
Value-BasedPriceBenchmark
FH(n=453,443) $5,700/yr $8,000/yr $10,278/yr $5,700-$8,000/yrCVDstatin-intolerant(n=364,948)
$5,800/yr $8,300/yr $12,896/yr $5,800-$8,300/yr
CVDnotatLDLgoal(n=1,817,788)
$5,300/yr $7,600/yr $2,976/yr $2,976/yr
Total(n=2,636,179)
$5,404/yr $7,735/yr $2,177/yr $2,177/yr
FH:familialhypercholesterolemia;CVD:cardiovasculardisease;LDL:low-densitylipoprotein;QALY:quality-adjustedlifeyearAuthor’sdiscussion
• PCSK9inhibitorsmaysubstantiallyreducenon-fatalMIs,non-fatalstrokes,andcardiovasculardeathoveralifetime
• PCSK9inhibitorsgeneratedICERsthatexceedcommonly-acceptedthresholds• An85%reductioninlistpricewouldbenecessarytoavoidaddingexcessivecostburdenstothe
healthcaresystemReviewer’scritique
• CVDmodelnotapplicabletopatients<35yearsold• FHdiagnosisnotin-linewithcurrentrecommendationsfordiagnosis• UsedhistoricLDLtreatmentgoalvaluesnolongerstandardofcare• Tenpercentstatinintolerancerateisanoverestimation• Outcomeeventreductiondoesnotreflectresultsfromrecentstudies• DrugeffectsonCVDwerebasedonLDLreductionalone• Sensitivityanalysesofbasecasesconsistentlysensitivetolowerpriceandlongeranalysishorizon• Usedarbitrarybudgetimpactthresholdthatdoesnotreflectrealworldpolicy
13. ICERreportsummary39
a. ICERmodeledPCSK9useinstatintolerantandintolerantpatientsi. Comparedtoezetimibeuseii. Baselinestatinuse
b. Utilizedacost-benefitanalysistocomparevalueofezetimibeandPCSK9inhibitorsasadd-ontherapiesc. ICERfindsPCSK9inhibitorsonlyviableastreatmentoptionswithoutrestrictionatapriceof$2,177—aprice
lessthanthecurrentAWPofezetimibed. Findingsarebasedonquestionablemodelingofpopulationandeventratese. Costsmisspotentiallysignificanteventsavoided
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Conclusion14. Clinicalsummary40,41
a. PCSK9inhibitorssignificantlydecreaseserumLDLcholesteroli. EvolocumabdecreasedLDLby~61%at48-weeksii. AlirocumabdecreasedLDLby61%at24weeks,and58%at78weeks
b. LDLcholesterollevelsbelow70mg/dLmayresultinfurtherimprovedCVDoutcomesi. MeanabsoluteLDLlevelwas48mg/dLat24weeksoftherapyinODYSSEY
c. Interimanalysesindicateadditional48-53%eventreductionwhenaddedtostatintherapyd. Studiesofsafetyconcludeneitherdrugpossessesasignificantadverseeffectprofile
i. Similarratesofadverseeventsleadingtodiscontinuationwereobservedbetweenalirocumabandplacebo,respectively:
ii. SlightlyhigherratesofneurocognitiveeventswithPCSK9inhibitorscomparedtoplacebo(notstatisticallysignificant)
e. Interimoutcomesanalysestrendingtowardssignificanteventreduction
15. Costsummary39a. PCSK9inhibitorsprojectedtobecostliestdrugclassinhistoryatcurrentaveragewholesaleprices(AWPs)
i. PraluentAWP:$14,600/yearii. RepathaAWP:$14,100/year
b. ICERfindings:i. ICERsatlistpricerangefrom$274,00-$302,00perQALYformodeledpopulationsii. Limitingusetoonlypost-MIpatientsstillresultsincosts>$150,000/QALYiii. ConcludedclassisviableatalowerpricethancurrentAWPforZetia®iv. Markedflawsinmodelingandcostassumptions
c. Emergingpay-for-performancedealscompensatepayersforunmetclinicaloutcomes
16. Clinicalrecommendationsa. Reserveasadd-onagentsinpatientswithgenetically-confirmedFHafterinitiatingstatintherapy
i. PrimarypreventioninpatientswithHoFHii. Primarypreventioninpatientswithhigher-riskHeFHiii. SecondarypreventioninmostpatientswithHeFH
b. Reserveasadd-onagentsforsecondarypreventioninhigh-riskpatientswithoutFHc. Keepawatchfuleyeonoutcomesdatalikelytobemadeavailableby2017
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AppendixAppendix1:Selectstudiesassessingstatin-inducedLDL-loweringandCVDoutcomes18-20,45-53
Trial N Intervention MeanbaselineLDL(mg/dL)
MeanLDLreduction
CVDeventreductionrate
NNT
Placebocontrolled4S(1994) 4444 Simvastatin20mg 188 35% 34%(p<0.0001) 15WOSCOPS(1996) 6595 Pravastatin40mg 192 26% 31%(p<0.001) 42AFCAPS/TEXCAPS(1998)
6605 Lovastatin20-40mg 150 25% 37%(p<0.001) 24
MIRACL(2001) 3086 Atorvastatin80mg 124 58% 16%(p=0.048) 39ALLHAT-LLT(2002) 3638 Pravastatin40mg 146 28% 9%(p<0.96) 43HPS(2002) 20536 Simvastatin40mg 131 30% 23%(p<0.0001) 19CARDS(2004) 2838 Atorvastatin10mg 117 40% 37%(p<0.001) 24ASPEN(2006) 2410 Atorvastatin10mg 113 30% 10%(NS) 4MEGA(2006) 8214 Pravastatin10-20mg 157 18% 33%(p=0.01) 6SPARCL(2006) 4731 Atorvastatin80mg 133 42% 26%(p<0.001) 15JUPITER(2008) 17802 Rosuvastatin20mg 108 50% 44%(p<0.00001) 82StatincomparativeefficacyPROVEIT-TIMI22(2004)
4162 Atorvastatin40mgvs.pravastatin40mg
106vs.106 95vs62mg/dL
16%(p<0.005) 2
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