Jurnal Menopause Ku

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ContentslistsavailableatScienceDirect

Maturitas

j ourna l h o me pa g e :w w w . e l s e v i e r . c o m / l o c a t e / m a t u r i t a s

Mini

review

Perspective

on

prescribing

conjugated

estrogens/bazedoxifene

for

estrogen-deﬁciency

symptoms

of

menopause:

A

practical

guide

Santiago

Palacios

a∗

,

Heather

Currie

b

_,

_Tomi

_S.

_Mikkola

c

_,

_Erika

_Dragon

d

a_Instituto_Palacios,_Madrid,_Spain

b_NHS_Dumfries_&_Galloway,_Dumfries,_Scotland,_United_Kingdom c_Helsinki_University_Central_Hospital,_Helsinki,_Finland d_Pﬁzer,_Global_Innovative_Pharma,_Europe,_Paris,_France

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received30October2014

Receivedinrevisedform9January2015 Accepted11January2015

Availableonlinexxx Keywords: Menopause Hotﬂashes

Postmenopausalhormonereplacement therapy

Selectiveestrogenreceptormodulators (SERMs)

Bazedoxifene Osteoporosis

a

b

s

t

r

a

c

t

Currentguidelinesrecommendthathormonetherapy(HT)inpostmenopausalwomenwithauterus includeaprogestintoprotectagainstendometrialhyperplasia.However,manyconcernsrelatingtoHT useappeartoberelatedtotheprogestincomponent,includingcardiovascularrisk,breaststimulation,and irregularvaginalbleeding.Conjugatedestrogens(CE)combinedwiththeselectiveestrogenreceptor mod-ulatorbazedoxifene(BZA)isanewprogestin-freeHToptionforalleviatingestrogendeficiencysymptoms inpostmenopausalwomenwithauterusforwhomtreatmentwithprogestin-containingtherapyisnot appropriate.Fivedouble-blind,randomized,placebo-controlled,phase3studies,knownastheSelective estrogens,Menopause,AndResponsetoTherapy(SMART)trialshaveinvestigatedtheefficacyofCE/BZA forrelievingvasomotorsymptoms(VMS),andeffectonbonemass,aswellasendometrialandbreast safetyinpostmenopausalwomen.Ina12-weekstudy,CE0.45mg/BZA20mgsignificantlyreducedthe numberandseverityofhotflushescomparedwithplaceboatweeks4and12.Unlikeestrogen-progestin therapy(EPT),CE0.45mg/BZA20mgdidnotincreasebreastdensitycomparedwithplacebo.In clini-caltrialsupto2years,CE/BZAhadafavorabletolerabilityprofile,demonstratedbyamenorrhearates similartoplacebo.Vasculardisordersincludingvenousthromboembolicevents(pulmonaryembolism, retinalveinthrombosis,deepveinthrombosis,andthrombophlebitis)wererareevents,occurringinless than1per1000patients.CE/BZAwasassociatedwithsignificantlyhigherincidencesofamenorrheaand lowerincidencesofbleedingcomparedwithCE/medroxyprogesteroneacetatein2comparativetrials. Therefore,CE0.45mg/BZA20mgprovidesaneffective,well-tolerated,progestin-freealternativetoEPT forpostmenopausalwomenwithauterus.

Contents

1. Introduction... 00

2. EfﬁcacyofCE/BZAinphase3clinicaltrials... 00

3. Safetyandtolerabilityconcernsandcontraindications ... 00

4. AppropriatecandidatesforCE/BZAtherapy... 00

5. Conclusion... 00 6. Practicepoints... 00 7. Researchagenda... 00 Disclosures... 00 Contributors... 00 Competinginterest... 00

∗ Correspondingauthor.Tel.:+34915780517;fax:+34914319951. E-mailaddress:[email protected](S.Palacios).

http://dx.doi.org/10.1016/j.maturitas.2015.01.003

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Provenanceandpeerreview... 00 Acknowledgments... 00 References... 00

1. Introduction

Hormonetherapy(HT)isestablishedasthemosteffective ther-apyfor vasomotorsymptoms(e.g.,hotflushes, nightsweats)in womenyoungerthan60years[1].Theadditionofaprogestogen tosystemicestrogen(estrogen-progestintherapy[EPT])is recom-mendedfornonhysterectomizedwomentopreventendometrial cancer[2].ManyconcernsaboutHTappear toberelatedtothe progestin component, as coronaryheart diseaserisk, increased mammographicbreastdensity,breastcancerrisk,breastpain,and irregularvaginalbleeding occurmorefrequentlywithEPTthan withestrogentherapy(ET)[3–6].Thus,thereisaneedfor progestin-free treatment options that protect the endometrium, with a clinicallyevidencedefficacyandimprovedtolerability/safety pro-file.

Conjugated estrogens (CE)/bazedoxifene (BZA) (CE/BZA; Duavive®,Duavee®)isanoveltissueselectiveestrogencomplex (TSEC) combining estrogens with a selective estrogen receptor modulator (SERM). The rationale for TSEC development was that the SERM component would minimizeadverse estrogenic effects on theendometrium and breast, while maintainingthe beneficialeffectsofestrogensonmenopausalsymptoms[7].BZA wasspecificallyselectedasthisSERMbecauseitshowedfavorable preclinicaleffectsontheskeleton,vasomotor activity,and lipid metabolism,as well as mammary and uterine safety [8]. Gene expressionprofilingofCEincombinationwith3differentSERMs (BZA,raloxifene,and lasoxifene)showeddifferentialpatternsof geneexpression,indicatingthatdifferentSERM/CEcombinations may have distinct clinical activities [9]. Preclinical data have shownthatwhereas CEalone stimulatesproliferationofMCF-7 andT47Dhumanbreastcancercellsandreducescellapoptosis, theaddition of BZA at anadequate doselevel abrogatesthese effects[10].In aseparateanalysis,BZAwasalsoshowntobea morepotentinhibitorofCE-dependentinvitrobreastcancercell proliferationthanraloxifeneandlasoxifene.Aphase3studyofBZA aloneinpostmenopausalwomenwithosteoporosisdemonstrated afavorablelong-termsafetyprofileintheendometrium,breast, andreproductivetractover7years[11].

2. EfﬁcacyofCE/BZAinphase3clinicaltrials

CE0.45mg/BZA20mgoncedailytablet(Duavive®)wasrecently approvedintheEuropeanUnionfortreatmentofestrogen defi-ciencysymptomsinpostmenopausalwomenwithauterus(≥12 monthssince lastmenses)forwhomtreatmentwith progestin-containingtherapyisnotappropriate[12].CE0.45mg/BZA20mg isalsoapprovedintheUnitedStates(Duavee®)fortreatmentof moderatetoseverevasomotorsymptoms(VMS)associatedwith menopauseandpreventionofpostmenopausalosteoporosis[13]. Safetyand efficacyof CE/BZAare supportedby5 double-blind, randomized, placebo- and active-controlled, phase 3 Selective estrogens,Menopause,AndResponsetoTherapy(SMART)trials (Table 1) [14–20]. In SMART-2, CE 0.45mg/BZA 20mg signifi-cantlyreducedthemeandailynumberofmoderatetoseverehot flushes by74% at week12, and significantly reduced hot flush severityduringweeks3through12(p<0.001vsplacebo)[15].In SMART-3,CE0.45mg/BZA20mgsignificantlyincreased superfi-cialcells,decreasedparabasalcells,andreducedvaginaldryness comparedwithplaceboinpostmenopausalwomenwithmoderate toseveresymptomsofvulvar-vaginalatrophy(VVA)atbaseline;

however,themostbothersomeVVAsymptomandvaginalpHwere notstatisticallysignificantlyaffectedversusplacebo[16].Inthe 1-yearSMART-5study,CE0.45mg/BZA20mgshowedanincreaseof 0.24%frombaselineinlumbarspineBMDatmonth12compared withadecreaseof1.28%forplacebo—asignificant(p<0.01) dif-ferenceof+1.52%[18].CE/BZAalsoexhibitedbeneficialeffectson sleepparametersandmenopause-relatedqualityoflife[18,20,21].

3. Safetyandtolerabilityconcernsandcontraindications

CE/BZAwaswelltoleratedintheSMARTtrials;ratesof discon-tinuationduetoadverseeventswerelowandsimilartoplacebo (Fig.1[SMART-5])[15–19].Higherbreastdensityhasbeenshown tobeassociatedwithlowermammographicsensitivity(i.e.,ability todetectcanceratscreening)[22].IntheSMART-5study,mean mammographicbreastdensitydecreasedtoacomparableextent frombaselineto1yearwithCE/BZA(−0.38%)andplacebo(−0.44%) whileHT(CE/MPA)signiﬁcantly(p<0.001)increasedbreastdensity (+1.60%)frombaselinecomparedwithplacebo[23].Similar reduc-tionsinbreastdensitywerereportedforCE/BZAandplaceboat 2yearsinanancillarystudytoSMART-1[24].Incidenceofbreast cancerwaslowandsimilartoplaceboduringupto2yearsofusein theSMARTtrials[23,24].Theincidenceofbreastpain/tenderness amongwomentreatedwithCE/BZAwassimilartoplaceboacross SMARTtrials[15–19]andsigniﬁcantlylowerthanwithCE/MPAin SMART-4andSMART-5[17,18].

TheadditionofBZAtoCEreducestheriskofendometrial hyper-plasiathatcanoccurwithestrogen-onlyuse[12].Through12-and 24-monthfollow-upintheSMARTtrials,therewasnoincreased riskofendometrialhyperplasiawithCE0.45mg/BZA20mg[14,18]. Incidencesofuterinebleedingandspottingwerelowandsimilar toplacebo[17,18,25].InSMART-4andSMART-5,CE0.45mg/BZA 20mgwasassociatedwithasigniﬁcantlyhigherrateofamenorrhea (Fig.2[SMART-5])andlowerincidenceofbleedingcomparedwith CE/MPA[17,18].Inonestudy,amenorrheawasreportedin97%of thewomenwhoreceivedCE0.45mg/BZA20mgduringmonths10 to12[12].AswithotherHT,abnormalbleedingrequires diagno-sisbeforeinitiatingCE/BZA,andanypersistent/recurrentbleeding duringtreatmentwarrantsinvestigationtoruleoutmalignancy.

AlthoughCEandBZAindividuallyhavebeenlinkedtoincreased venousthromboembolism(VTE)risk[26,27],thereappearstobeno addedriskofcombiningthetwo.Acrossallthephase3studies,VTE wasarareevent,affectinglessthan1personper1000patients[12]. There were few VTEs in the SMART studies (CE 0.45mg/BZA 20mg:n=3;placebo:n=1;alldeepveinthromboses)[15–19,28]. Although the rates of myocardial infarction with CE/BZAwere similartoplacebointheSMARTtrials,effectsofCE/BZA(Fig.2) onthecardiovascularsystemrequirefurtherdatacollectionand analysis.Innonhumanprimates(postmenopausalmonkeys)feda high-fat,high-cholesteroldiet,CEmodestlyreducedtheseverity ofatherosclerosisandcomplicatedplaquesinthecommoncarotid artery;theadditionofBZAdidnot signiﬁcantlyattenuatethese beneﬁts[29].StatisticalpowertoevaluateVTEand cardiovascu-larrisksislimitedbythesmallnumberofsucheventsandlack oflong-termfollow-updatafromtheSMARTtrials.Ifprolonged immobilizationisanticipatedfollowingelective surgery,CE/BZA should bestopped temporarily beginning 4 to 6 weeks before surgery[12].Treatmentshouldnotberestarteduntilthewomanis completelymobilized[12].

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Table1

StudydesignsoftheSMARTtrials.

SMART-1[14] SMART-2[15] SMART-3[16] SMART-4[17] SMART-5[18]

N(randomized) 3544 332 652 1083 1886

Keyeligibilitycriteria Postmenopausalwomenwithauterus

Aged40to75years Aged40to65years Aged40to65years Aged40to65years Aged40to65years ≥7moderatetosevere

dailyhotﬂushes

≥1moderatetosevere VVAsymptoms

Studyduration 2years 12weeks 12weeks 1year(1-yearextension) 1year Treatmentsadministered

(once-dailyoraldoses)

•CE0.625or0.45mg eachwithBZA10,20, or40mg •Raloxifene60mg •Placebo •CE0.45mg/BZA20mg •CE0.625mg/BZA20mg •Placebo •CE0.45mg/BZA20mg •CE0.625mg/BZA20mg •BZA20mg •Placebo •CE0.45mg/BZA20mg •CE0.625mg/BZA20mg •CE0.45mg/MPA1.5mg •Placebo •CE0.45mg/BZA20mg •CE0.625mg/BZA20mg •BZA20mg •CE0.45mg/MPA1.5mg •Placebo

Primaryendpoints •Incidenceof endometrial hyperplasia •Frequency/severity ofhotﬂushes •Vaginalmaturation •VaginalpH •Mostbothersome symptom •Incidenceof endometrial hyperplasia •Bonemineraldensity

•Incidenceof endometrial hyperplasia •Bonemineraldensity Secondaryendpoints •Bonemineraldensity

•Boneturnovermarkers •Frequency/severityof hotflushes •VVAmeasures •Sleep •Menopause-specific qualityoflife •Sleep •Menopause-specific qualityoflife •Breastpain •IndividualVVA symptoms(dryness, itching/irritation, dyspareunia) •Sexualfunction •Satisfactionwith treatment •Menopause-specific qualityoflife •Amenorrheaprofile •Breastpain •Osteoporosis parameters •Bleeding •Breastdensity •Breasttenderness •Sleep •Menopause-specific qualityoflife

SMART,Selectiveestrogens,Menopause,AndResponsetoTherapy;VVA,vulvar-vaginalatrophy;BZA,bazedoxifene;CE,conjugatedestrogens;MPA,medroxyprogesterone acetate.

CE/BZA had favorable effects on lipid profile in the SMART trials, significantly lowering total and low-density lipoprotein cholesterol,whileincreasinghigh-densitylipoproteincholesterol, comparedwithplacebo[15,16,19].CE/BZAhadminimaleffectson coagulationprofile,consistingofsmalldecreasesfrombaselinein fibrinogenandplasminogenactivatorinhibitortype1 activities, andsmallincreasesinplasminogenactivity[19].Inpooledanalyses

oftheSMARTtrials,CE/BZAwasnotassociatedwithincreasesin bodyweightorbodymassindexcomparedwithplacebo[30].

4. AppropriatecandidatesforCE/BZAtherapy

CE/BZA was studied in healthy nonhysterectomized post-menopausal women, on average 53 to 56 years of age

Fig.1.SummaryofselectedsafetyandtolerabilityparametersinSMART-5[18].a_Overall_p_<_0.05.b_Overall_p_<_0.001._AE,_adverse_event;_CE,_conjugated_estrogens;_BZA,

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Fig.2. Ratesofcumulativeamenorrheaforcycles1to13amongpostmenopausalwomentakingCE/BZA,BZA,CE/MPA,orplaceboinSMART-5.Reprintedwithpermission fromendocrinesociety[18].a_P_<_0.001_vs_all_other_treatment_groups.

CE,conjugatedestrogens;BZA,bazedoxifene;MPA,medroxyprogesteroneacetate.

Table2

CharacteristicsofwomenenrolledintheSMARTtrials[14–18,20].

Characteristic Eligibilitycriteria Averageparticipanta

Healthywomenpostmenopausalwomenwithintactuterus

Age 40to65years

(SMART-1:40to75years)

53to56years

BMI ≤34kg/m2_(≤32.2_kg/m2_in_SMART-1) ₂₅_to₂₆_kg/m2

Race All Caucasian:76%to94%

Timesincelastnaturalmenstrualperiod ≥12monthsor≥6months withappropriateFSHlevel

∼4to8years Vasomotorsymptoms(SMART-2) ≥7moderatetoseverehotﬂushesperdayor50hot

ﬂushesperweek

∼10moderateandseverehotﬂushesperday Vulvar-vaginalatrophysymptoms(SMART-3) ≥1moderatetoseverevulvar-vaginalsymptom(vaginal

dryness,irritation/itching,orpainwithintercourse)

Mostbothersomesymptom: Painwithintercourse:43%to59% Vaginaldryness:30%to41% Vaginalitchingorirritation:11%to16% Vaginalcytologicalsmear:≤5%superﬁcialcells 0.8%to1.0%superﬁcialcells

VaginalpH:>5 VaginalpH:∼6.2

BMI,bodymassindex;FSH,folliclestimulatinghormone;SMART,Selectiveestrogens,Menopause,AndResponsetoTherapyTrial.

a_Based_on_mean_baseline_{characteristic}_across_groups.

(Table2)[14–18].EfficacyofCE/BZAforVMShasbeen demon-stratedinwomenexperiencingatleast7moderatetoseverehot flushesperdayatbaseline[15].Thus,werecommendCE/BZAfor womenwithfrequent,bothersomehotflushes.

CE/BZAcanbeconsideredinwomenforwhomprogestinsare inappropriateorforwhomthebenefit-riskprofileisassessedas favorablecomparedwithprogestin-containingHT. Recommenda-tionsabout whichtousecannot bemadebasedonefficacy,as therearefewdirectcomparisonsbetweenCE/BZAandEPT.CE/BZA maybeconsideredforwomenwhohaveexperiencedbothersome vaginalbleeding or breast pain/tenderness, orother intolerable sideeffectsofprogestin-containingtherapy(e.g.,nausea,hirsutism, headache, dizziness, weight gain). In addition, exogenous pro-gestinshave beenassociated withcyclical mild depression and moodsymptomssimilartothoseofpremenstrualsyndromeor pre-menstrualdysphoricdisorderinpostmenopausalwomen[31,32]. Oral progestin-containing therapy is associated withdecreased glucosetoleranceandincreasedinsulinresistance[33,34].Unlike ET,EPThasbeenassociatedwithincreasedbreastdensity[4,35], whichmayimpedemammographicdetectionofbreastcancerand serveasanindependentriskfactorforbreastcancer[36]. Further-more,giventheWomen’sHealthInitiativetrialresultsshowingan increasedriskofbreastcancerinwomentakingEPTcomparedwith ET[3],somewomenmaydeclineprogestin-containingHTbased onconcernsaboutbreastcancerrisk.Such womenmaywishto

considerprogestin-freetreatmentwithCE/BZA,withthe under-standingthatlong-termdataonbreastcancerriskarenotcurrently available.

5. Conclusion

CE/BZAisaneffective,progestin-freetreatmentfor menopause-relatedhotflushes.UnlikeEPT,CE/BZAdoesnotincreasebreast density.At10to12months,amenorrheawasreportedinabout97% ofthewomenwhoreceivedCE/BZA,aratesimilartoplacebo[12]. Acrossallthephase3studies,VTEwasarareeventaffectingless than 1 person per 1000 patients. Thus, CE/BZAfills an impor-tant needfor a progestin-freealternative totraditional EPT for nonhysterectomizedpostmenopausalwomen whocannot toler-ateprogestin-containingtherapyorwhowishtoavoidpotential safetyconcernsassociatedwithprogestins.However,when com-paringthesafetyprofilesofprogestin-containingtherapyversus CE/BZA,itshouldbekeptinmindthatlong-termsafetydatafor CE/BZAarenotyetavailable.

6. Practicepoints

• CE/BZAisanovel,progestin-freetreatmentoptionformanaging symptomsofestrogendeﬁciencyinnonhysterectomized post-menopausalwomen.

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• CE/BZAshouldnotbeusedinwomenwithundiagnosed abnor-malbleeding,knownorsuspectedbreastcancer,orspontaneous venousorarterialthromboembolism.

• UnlikeEPT,CE/BZAdoesnotincreasebreastdensity.

• CE/BZAcanbeconsideredinwomenforwhomprogestinsare inappropriateorforwhomthebeneﬁt-riskproﬁleisassessedas favorablecomparedwithprogestin-containingHT(e.g.,women withdepression,insulinresistance,thosewhoexperienced both-ersomesideeffectsonprogestin-containingtherapy).

7. Researchagenda

• Menopausalsymptomsarechronicandoftentreatedfor≥5years. DataonbreastcancerriskandothersafetyoutcomesofCE/BZA usebeyond2yearsareneeded.

• FurtherstudyonVTEriskisneededtoconﬁrmthelowincidence seenintheSMARTstudies.

• FurthercomparativerandomizedcontrolledtrialsofCE/BZAvs EPTareneededtoinformtreatmentselection.

Disclosures

SPalacioshasbeena symposiumspeakeror advisoryboard memberforServier,Pfizer,GSK,Abbott,Ferrer,Bioiberica,Shionogi and Amgenandhasreceivedresearch grantsand/orconsulting feesfromPfizer,Servier,Amgen,MSD,Preglem,LeonFarma,and Gynea.HCurriehasreceivededucationalgrantsandspeakerfees, andhasbeenanadvisoryboardmemberforseveralpharmaceutical andnonpharmaceuticalcompanies.TMikkolahasbeenaspeaker and/orreceivedconsultingfeesfromAMS,AstellasPharma,Bayer, BostonScientific,NovoNordisk,andPfizer.EDragonisanemployee ofPfizerInc.

Contributors

SantiagoPalacios,HeatherCurrie,TomiS. Mikkola,andErika Dragoncontributedequallytotheconceptionofthispaper, criti-callyreviseditforimportantintellectualcontent,andapprovedthe ﬁnalversionsubmitted.

Competinginterest

SPalacioshasbeena symposiumspeakeror advisoryboard memberforServier,Pfizer,GSK,Abbott,Ferrer,Bioiberica,Shionogi and Amgenandhasreceivedresearch grantsand/orconsulting feesfromPfizer,Servier,Amgen,MSD,Preglem,LeonFarma,and Gynea.HCurriehasreceivededucationalgrantsandspeakerfees, andhasbeenanadvisoryboardmemberforseveralpharmaceutical andnonpharmaceuticalcompanies.TMikkolahasbeenaspeaker and/orreceivedconsultingfeesfromAMS,AstellasPharma,Bayer, BostonScientific,NovoNordisk,andPfizer.EDragonisanemployee ofPfizerInc.

Provenanceandpeerreview

Provenanceandpeerreview:Commissionedandexternallypeer reviewed.Thisisaminireview.

Acknowledgments

MedicalwritingassistancewasprovidedbyLelaCreutz,PhDand LaurenCerruto,ofPelotonAdvantage,LLC(supportedbyPﬁzer).

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