Which Drug to Discontinue 3 Months After Combination Therapy of Tadalafil plus Tamsulosin for Men with Lower Urinary Tract Symptom and Erectile Dysfunction? Results of a Prospective Observational Trial

Benign

Prostatic

Obstruction

Which

Drug

to

Discontinue

3

Months

After

Combination

Therapy

of

Tadalafil

plus

Tamsulosin

for

Men

with

Lower

Urinary

Tract

Symptom

and

Erectile

Dysfunction?

Results

of

a

Prospective

Observational

Trial

Arcangelo

Sebastianelli

,

Pietro

Spatafora

,

Jacopo

Frizzi

,

Omar

Saleh

,

Cosimo

De

Nunzio

,

Andrea

Tubaro

,

Linda

Vignozzi

,

Mario

Maggi

,

Sergio

Serni

,

Kevin

T.

McVary

,

Steven

A.

Kaplan

,

Stavros

Gravas

,

Christopher

Chapple

,

Mauro

Gacci

*

a_{DepartmentofMinimallyInvasiveandRoboticUrologicSurgeryandKidneyTransplantation,UniversityofFlorence,Florence,Italy;}b_Departmentof

Urology,Sant’AndreaHospital,University“LaSapienza”,Rome,Italy;c_{DepartmentofClinicalPhysiopathology,UniversityofFlorence,Florence,Italy;}d_Center

forMaleHealth,DepartmentofUrology,StritchSchoolofMedicine,LoyolaUniversityMedicalCenter,Maywood,IL,USA;e_{DepartmentofUrology,Icahn}

SchoolofMedicineatMountSinai,NewYorkCity,NY,USA;f_{DepartmentofUrology,UniversityofThessaly,Larissa,Greece;}g_{DepartmentofUrology,Sheffield}

TeachingHospitalsNHSTrust,Sheffield,UK

a v ai l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n al h o m e p a g e : w w w . e u r o p e an u r o l o g y . c o m / e u f o c u s Articleinfo Articlehistory: AcceptedSeptember24,2019 AssociateEditor: Dr.MalteRieken Keywords:

BenignProstaticObstruction BenignProstaticHyperplasia ErectileDysfunction

lowerurinarytractsymptoms combinationtherapy

tadalafil tamsulosin

Abstract

Background: Safety and efficacy of tamsulosin and tadalafil for men with benign prostatic enlargement (BPE)and/or erectiledysfunction (ED) aredefined. However, thereareonlyafewpilotstudiesoncombinationtherapywiththesedrugsformenwith lowerurinary tractsymptom(LUTS)/BPEand ED.Moreover,preliminary reportsare limitedto12wk,withoutanyinformationaboutsubsequenttherapies.

Objective: To evaluate the impact of discontinuation of tamsulosin versus tadala_fil 12wkaftercombinationtherapy.

Design,setting,andparticipants: Fiftyconsecutivepatientswithmoderate-to-severe LUTS(InternationalProstateSymptomScore[IPSS]>7)andmild-to-severeED (Inter-national Indexof Erectile Function-5 [IIEF-5] <22) weretreatedwith combination therapy(tamsulosin0.4mg/dplustadala_fil5mg/d)for12wk.After12wk,25patients discontinuedtamsulosin(GroupTAD),while25patientsdiscontinuedtadalafil(Group TAM).

Outcomemeasurements and statisticalanalysis: Efficacy variables wereIPSS (total, voiding,storage)andIIEF-5.Pairedsamplesttestandanalysisofvariancewereused. Resultsandlimitations: Groups TADand TAMpresented similarfeatures (age,BMI, metabolic profile) including symptoms scores at baseline. Similar and significant improvementsinIPSS(total,voiding,andstorage) andIIEF-5wererecordedin both groups after 12 wkof combination therapy (all p< 0.001). Total IPSS was similar betweenthetwogroupsattheend ofthetrial.However,wefoundbetween-group signi_ficantdifferencesfrombaselineto24wkandfrom12to24wkinstorage-IPSS (Group TAD: –3.32 vs Group TAM: –1.24, p= 0.002; Group TAD: +0.24 vs Group

*Correspondingauthorat:DepartmentofMinimallyInvasiveandRoboticUrologicSurgeryand

KidneyTransplantation,UniversityofFlorence,LargoBrambilla3,Florence,50134,Italy.

Tel. +39 055 275 8011, Fax: +39 055 275 8014.

E-mail addresses:maurogacci@yahoo.it,maurogacci@aou-careggi.toscana.it(M. Gacci).

https://doi.org/10.1016/j.euf.2019.09.015

1. Introduction

Lowerurinarytractsymptoms(LUTSs)anderectile dysfunc-tion(ED)aresignificanthealthconcernsthatwillincreasein thenextyears inrelation to theagingof thepopulation. Both conditions have a significant impact on the overall malequalityoflife(QoL).LUTS,includingvoiding,storage, andpostmicturitionsymptoms,secondarytobenign pros-tatic hyperplasia (BPH) isfrequently reported in middle-agedoroldermen.Theyrangefrommildtosevereandcould haveamajorimpactonpatients’QoL[1,2].

ED, defined as a persistent inability to achieve and maintainanerectionsufficientforsatisfactorysexual per-formance,isgenerallyconsideredtheresultofpara-aging factorsanditsprevalencehasincreasedfrom5%formenin theirfortiesto15%forthoseaged70yr[3].

Severallarge-scale epidemiologicalstudies indifferent populationhavedemonstratedarelationshipbetweenLUTS andEDinagingmenthatisindependentoftheeffectsofage orothercomorbidities;particularly,menwithsevereLUTS presentedanincidenceofEDaboutthreetimeshigherthan thosewithoutLUTS[1,4].

Today, although the molecular and pathological pathwayspotentiallylinkingLUTSandEDarenotclearly defined,severalpossiblebiologicalmechanisms includ-ing an altered nitricoxide/cyclic guanosine monopho-sphate pathway,an alteredRhoA/Rho kinasesignaling, systemic inflammation, pelvic ischemia, autonomic adrenergic hyperactivity, or overactivity have been investigated [5–8].

LUTS/BPHmedicaltreatmentmayalsohaveasignificant impactonerectilefunction(EF).Severalrandomized con-trolledtrialsdemonstratedthatalpha-blockers(ABs)and 5-alphareductaseinhibitors,themostcommonlyprescribed drugsformanagingpatientswithLUTS/BPH,canbe associ-atedwithsexualadverseeffects(AEs)suchasdecreasedor lossoflibido,ED,andejaculatorydysfunction[9–11].

Phosphodiesterasetype5inhibitors(PDE5-Is),the first-line therapy for ED, and particularly tadalafil5mg once daily,havebeenapprovedandconsideredaneffectiveand well-toleratedtreatmentforLUTS[10].

AlthoughtheexactmechanismofactionofPDE5-Isremains unclear,severalpreclinicalandclinicaltrialshaveshownthat theycanreducethesmoothmuscletoneofdetrusor,prostate, andurethratogetherwithanincreasedbloodperfusionand oxygenationinthelowerurinarytract;besides,itspossible

effectonchronicinflammationintheprostateandbladderhas beenproposed[12–15].

Safety and efficacy of PDE5-Is are well defined and combinationtherapyofPDE5-IsandABs,particularly tam-sulosin,theonlyABapprovedbytheFoodandDrug Admin-istrationincombinationwithtadalafil,hasshowntohave anadditivefavorableeffectonInternationalProstate Symp-tomScore(IPSS),InternationalIndexofErectileFunction-5 (IIEF-5) score, andmaximum flow rate (Qmax) compared withmonotherapyalone[16].Sofar,therecentpossibility tomanagebothLUTSandEDbyPDE5-ialoneorin combi-nation with tamsulosin may open up new management strategies, considering that treatment of one condition may have an impact on the other. However, although a combinationtherapyisconsideredapromisingandtailored approachseekingabalancebetweenefficacyand tolerabil-ityinpatientswithLUTS,therearenodataonwhentomove fromasingle-drugmanagementtoacombinationapproach andwhatarethepossiblechangesinefficacybyswitching fromonetreatmentmodalitytoanother[17].

The aim of thisobservational study isto evaluate the impactofdiscontinuationoftamsulosin(0.4mg)or tada-lafil(5mg)after12wkofcombinationtherapyinpatients withLUTSandED.

2. Materialandmethods

2.1. Designandparticipants

A prospective observational trial was designed and per-formed. Across 12 mo, 50 consecutive patients with ED and LUTS suggestive of benign prostatic obstruction (BPO)wereenrolled.

Inclusion criteriawereage>40–80yr,mildtosevere ED(IIEF-5<22),moderatetosevereLUTS(IPSS>7),and Qmax > 5ml/s (obtained from a uroflowmetry assess-ment). Exclusioncriteria were hypersensitivity to tada-lafil or tamsulosin, prostatic cancer or suspected with prostate-specific-antigen > 4.0ng/ml, bladder lithiasis, previousprostaticsurgery,urinarytractinfection, neuro-genicbladder,finasterideordutasterideusewithin6mo, and aclinical historyof urethraland/or provenbladder neckobstruction.

Thestudywasperformedinaccordancewithapplicable laws and regulations,good clinical practices,and ethical principles as described in the Declaration of Helsinki.

TAM: +1.20, p= 0.040, respectively) and in IIEF-5 (Group TAD: +4.64 vs Group TAM:+0.16,p<0.001;GroupTAD:–1.64vsGroupTAM:–4.40,p= 0.003).Nosignificant treatment-relatedadverseeventwasrecordedinbothgroups.

Conclusions: After12wkofcombinationtherapy,monotherapywithtadalafilforfurther 12wkallowstopreservetheimprovementofstorageIPSSandIIEF-5,inadditiontototal IPSS.

Patient summary: In this reportwe evaluated thediscontinuation of tamsulosin or tadalafilafter12wkofcombinationtherapy.Wefoundthattadalafilmonotherapy,fora further12 wk,aidsin retainingtheimprovement ofstoragesymptoms anderectile function.

InstitutionalReviewBoardsforeachsiteapprovedthestudy (EthicsCommitteeApprovalOSS.15.031).Allmenprovided writteninformedconsentbeforeinitiatinganytrial proce-dureortherapy.

The assessment of patients included age, body mass index,waistcircumference,bloodpressure,clinical labora-toryparameters,digitalrectalexamination,IPSS[18],IIEF-5 score[19],uroflowmetry,andpostvoidresidue(PVR) vol-ume (evaluated with abdominal ultrasound immediately aftervoidingforuroflowmetry).TheIPSSstorageand void-ingsubscores,nocturiaquestion,andIPSS-QoLindexwere alsoassessed.

Aftera4-wkwash-outperiodfromprevioustherapies forBPOanda2-wkrun-inperiodwithtamsulosin0.4mg, patientsweretreatedintwourologiccenterswith combi-nationtherapyoftamsulosin0.4mg/dandtadalafil5mg/d for12wk.

After12wk,thetamsulosintherapywasdiscontinued in onecenter, leaving 25 patients with tadalafil 5mg/d alone(GroupTAD),whereastadalafilwasdiscontinuedin the other center, leaving 25 patients with tamsulosin 0.4mg/donly(GroupTAM;Fig.1).

Patientswereevaluatedatscreeningtime,after12wkof combinationtherapy,andafter12wkofmonotherapy.

Patients were instructed to self-administer the study drugs at the same time every day before sleep, without restrictions of food intake or timing of sexual activity. Patientswere consideredcompliantif atleast90%of the drugamountwastaken.Safetywasassessedbyevaluating patient-reportedAEs,orthostaticvitalsigns,PVR, uroflow-metry, and clinical laboratory parameters. Patients with incomplete data sets were excluded from statistical analysis.

Thevariables consideredfor measuring theefficacy of treatmentwerethechangesinIPSSanditssubscores(total,

voiding,andstorage),themodificationofIIEF-5score,and the improving of Qmax. All follow-up visits, including uroflowmetry, were performed in the morning (from 8:00amto12:00pm).

2.2. Statisticalanalysis

Differences between combination therapy and the two groups switched to monotherapy were calculated by an unpaired sample t test at baseline, 12 wk, and 24 wk, respectively. Mean changes betweenbaseline and 12wk andthosebetween12and24wkwereassessedbyapaired sample t test for each treatment group. Between-group differences in change from baseline to 12 wk and from 12to24wkweremeasuredbyone-wayanalysisofvariance (ANOVA).AllstatisticalanalyseswereperformedwithSPSS (SPSSInc.,Chicago,IL,USA).Apvalueof0.05orlesswas consideredstatisticallysignificant.

3. Results

A total of 50 patients were treated with combination therapy of tamsulosin 0.4mg/d plus tadalafil 5mg/d for 12wk[20].Subsequently,25patientscontinuedtadalafil5 mg/d(GroupTAD)and25continuedtamsulosin0.4mg/d (Group TAM) only, for a further 12 wk. A Consolidated Standards of Reporting Trials (CONSORT) flowchart is shown in Fig. 1. All participants completed the study. Compliance with dosing requirements was over 90% in both groups. Bothtreatmentgroupswerewell balanced, withoutsignificantdifferencesinmetabolicfeatures,age, and BPO-related characteristics (Table 1). The overall improvement frombaseline to the firstcheckpoint after 12wkofcombinationtherapy(tadalafilplustamsulosin) was statisticallysignificant forallthe itemsevaluatedin

Enrolled Screened Not screened Excluded # Group TAM Tamsulosin 0.4 mg n = 25 Group TAD Tadalafil 5 mg n = 25 Follow-up 12 wk n = 25 Follow-up 12 wk n = 25 n = 82 n = 75 n = 7 Washout 4 wk Run-in 2 wk Tamsulosin 0,4 mg Patient decision = 5 Physician decision = 2

Group TAD + TAM Tadalafil 5 mg + Tamsulosin 0.4 mg

n = 50

Group TAD + PLA Tadalafil 5 mg + Placebo

n = 25

Follow-up 12 wk

n = 50

Fig.1–Dispositionofpatients.PatientConsolidatedStandardsofReportingTrials(CONSORT)diagram. PLA=placebo.

ourpopulation:total,voiding,andstorageIPSS;IIEF-5;and Qmax (allp< 0.001). Between-groupANOVA,comparing Group TAD only versus Group TAM only, did not show significant differences for total IPSS (p= 0.233), storage IPSS(p= 0.235),voidingIPSS(p= 0.02);IIEF-5(p= 0.412); andQmax(p= 0.908;Table2).AsshowninTable3,after 12wkofmonotherapy,astatisticallysignificantdifference wasfoundbetweenthetwogroupsformeanIPSSstorage score(Group TAD:+0.24vsGroup TAM:+1.2;p= 0.040;

Fig.2A),meanIIEF-5score(GroupTAD:–1.64ptsvsGroup TAM:–4.4;p= 0.003;Fig.2B),andmeanQmax(GroupTAD: –2.41ml/svsGroupTAM:–0.25ml/s;p= 0.001;datanot shown).Conversely,totalIPSSandvoidingIPSSwere simi-lar after the switch from combination to monotherapy (Fig.3Aand 3B).The proportionofpatients reportingat least one treatment-emergent AE (TEAE) was similar betweengroups(TAD:16%vsTAM:20%; Table4).TEAEs weremildtomoderateinseverity,withthemostcommon being headache and back pain. There were noclinically significant changesin laboratory measurements or vital signs. No urinary retention was reported. None of the patientsdiscontinuedtherapybecauseofaTEAE.

4. Discussion

Currently,therearefourPDE5-IsapprovedforEDtreatment which have beeninvestigated for the treatment of LUTS with or without ED in randomized double-blind clinical trials. In a recent meta-analysis, combination of PDE5-is andABsimprovedtheIIEF-5score(+3.6;p<0.001),IPSS (–1.8;p= 0.05),andQmax(+1.5ml;p< 0.001)when com-paredwithABsalone[21].

The authors concluded that, although the cost-effectiveness analysisofthistreatmentisneeded,PDE5-Isareeffectiveand welltoleratedeitheraloneorincombinationwithABs, partic-ularlyinyoungpatientswithsevereLUTS/BPH.Moreover,a recentprospectiveurodynamicstudyevaluatingtheimpactof dailytadalafil5mgonstorageandvoidingfunctioninmale BPHpatientsshowedthatmean bladderoutletobstruction indexsignificantlydecreasedfrom59.5atbaselineto45.7at 3mo(p= 0.001),andto42.9at12mo(p< 0.001)[22].

Thus,tadalafiloncedaily,aloneorincombinationwith tamsulosin,isincreasinglyprescribedinclinicalpracticeas an effective therapy for LUTS/BPE and concomitant ED

[23,24].

Table 1 –Patients’baseline characteristics.

GroupTAD(n=25) GroupTAM(n=25)

Meanstandarddeviation Minimum–Maximum Meanstandarddeviation Minimum–Maximum pvalue

Age(yr) 64.48.3 48–77 67.07.8 47–78 0.314

Weight(kg) 77.38.2 67–85 75.99.5 66–83 0.306

Bodymassindex(kg/m2

) 27.25.3 24–32 25.95.7 25–32 0.187 Abdominalobesity: waistcircumference(cm) 107.86.1 93–133 104.34.5 78–128 0.142 Triglycerides(mg/dl) 164.46.4 78–268 138.76.8 81–203 0.128 HDLcholesterol(mg/dl) 48.73.2 28–68 49.22.6 31–62 0.275 Glycemia(mg/dl) 123.24.5 79–224 107.75.7 79–215 0.124 IPSSbase 18.15.8 8–29 19.66.1 11–32 0.369

IPSSvoidingbase 8.34.3 1–16 8.93.4 5–20 0.537

IPSSstoragebase 8.83.2 0–14 7.93.2 2–13 0.354

IPSSQoLbase 3.90.9 3–6 3.81.2 2–6 0.686

IIEF-5base 12.34.0 6–21 11.83.2 6–18 0.587

Qmaxbase(ml/s) 14.03.8 8.4–23.0 11.84.1 3.4–19.7 0.55

HDL=high-densitylipoprotein;IIEF-5=InternationalIndexofErectileFunction-5;IPSS=InternationalProstateSymptomScore;Qmax=maximumurinaryflow

rate;QoL=qualityoflife.

Table 2 _–Change from baseline to 12 wk for Group TAD and Group TAM.

GroupTAD(n=25) GroupTAM(n=25) pvalue*

MeanIPSS12wk Delta3M(baseline–12wk) 10.4 –7.64 12.6 –6.96 0.233

MeanIPSSvoiding12wk Delta3M(baseline–12wk) 4.52 –3.76 5.72 –3.24 0.200

MeanIPSSstorage12wk Delta3M(baseline–12wk) 5.2 –3.56 5.48 –2.44 0.235

MeanIPSSQoL12wk Delta3M(baseline–12wk) 2.24 –1.72 2.04 –1.8 0.461 MeanIIEF-512wk Delta3M(baseline–12wk) 18.6 +6.28 16.88 +5.12 0.412 MeanQmax12wk Delta3M(baseline–12wk) 18.28 +4.27 13.97 +2.21 0.908

IPSS=InternationalProstateSymptomScore;IIEF-5=InternationalIndexofErectileFunction-5;Qmax=maximumurinaryflowrate;QoL=qualityoflife. *

Asexpected,ourresultsconfirmedasignificant improve-mentoftotalIPSS(–7),voidingIPSS(–3.5),storageIPSS(–3), IPSS-QoL(–1.8),IIEF-5 (+5.7),andQmax(+4.2ml/s;for all, p< 0.001)after12wkofcombinationtherapy.Indeed,as wepreviouslyreported,combinationtherapywas associ-atedwithabetterimprovementofQmaxandvoidingIPSS comparedwithtadalafilalone[20].

Interestingly, at the end of the study, after further 12 wk of monotherapy, patients in both groups shared similar totalIPSS,voidingIPSS,andIPSS-QoL scores, all clinically meaningful improvements when compared withbaseline.Indeed,Dongetal[25]showedthat tada-lafil alone seemed to be efficient to improve voiding subscore (–1.47) and IPSS-QoL (–0.35) compared with

Table 3 –Change from 12 wk to 24 wk for TAD and TAM groups.

GroupTAD(n=25) GroupTAM(n=25) pvalue*

MeanIPSS24wk Delta6M(12–24wk) 12.48 +2.08 14.32 +1.72 0.386

MeanIPSSvoiding24wk Delta6M(12–24wk) 6.2 +1.68 6.36 +0.64 0.456

MeanIPSSstorage24wk Delta6M(12–24wk) 5.44 +0.24 6.68 +1.2 0.040

MeanIPSSQoL24wk Delta6M(12–24wk) 2.88 +0.64 2.56 +0.52 0.628 MeanIIEF-524wk Delta6M(12–24wk) 16.96 –1.64 12.48 –4.4 0.003 MeanQmax24wk Delta6M(12–24wk) 15.87 –2.41 13.72 –0.25 0.001

IPSS=InternationalProstateSymptomScore;IIEF-5=InternationalIndexofErectileFunction-5;Qmax=maximumurinaryflowrate;QoL=qualityoflife. * _{Levelsofsignificancearecalculatedwithpairedsamplettest(p0.05).Thepvalueindicatesthelevelofsignificanceasperanalysisofvariance.}

(A)

(B)

IPSS storage IIEF-5

9 8.5 8 7 6 5 5.5 6.5 7.5 19 17 15 13 11 Baseline 12 wk 24 wk Baseline 12 wk 24 wk

Switch to tamsulosin Switch to tadalafil Switch to tamsulosin Switch to tadalafil

Fig.2–Changefrombaselineto24wkforGroupsTADandTAM.

GroupTAD=discontinuedtamsulosin;GroupTAM,discontinuedtadalafil;IIEF-5=InternationalIndexofErectileFunction-5;IPSS=International ProstateSymptomScore;Qmax=maximumurinaryflowrate.

(A)

(B)

IPSS total IPSS voiding

Switch to tamsulosin Switch to tadalafil Switch to tamsulosin Switch to tadalafil Baseline 21 19 17 15 13 11 9 9 10 8 7 6 5 4 3 12 wk 24 wk Baseline 12 wk 24 wk

placebo, althoughtheir results were not clinically rele-vant,because ameanchange less than 3points inIPSS wasrecorded.

Inourstudy, patients intheTAD groupexperienced a statisticallysignificantbutnotclinicallyrelevant(<1-point) changeinstorageIPSSwhencomparedwithpatientsinthe TAMgroup. However,in bothgroups weobserved a sta-tisticallyandclinicallysignificantimprovementfrom base-line.Ourresultsconfirmedthelong-termeffectofPDE5-i treatmentonLUTS,particularlystorageLUTSandthatthis effectismaintainedforatleast12wkwhen treatmentis suspended.

TheurodynamicfindingsofMatsukawaetal[22] sup-portourresults.Indeed,in49patientswhohaddetrusor overactivityduringcystometryatthebaselineassessment, uninhibited detrusor contractions disappeared in 15 (30.6%) after 3 mo (p= 0.02), and in 22 (44.9%) after 12mo(p< 0.001)oftreatmentwithtadalafil.

Moreover,tadalafilproved tobeanalternativeadd-on drugforpatientswithpersistentstorageLUTSrefractoryto

a

PatientsintheTAMgroupretainedtheimprovementof Qmaxachievedwithcombinationtherapy(13.97at12wkvs 13.72 at 24 wk). Conversely, a decrease of Qmax was observed in the TAD group (18.28 at 12 wk vs 15.87 at 24wk); however,animprovementofQmaxfrombaseline wasalsoobservedintheTADgroup(14.0vs15.87ml/s).

In contrast with our results, the first systematic review by Laydneret al [27]on theuse of PDE5-Is for BPE-related LUTS reported that PDE5-Isimproved IPSS andIIEF-5 butnotQmax.

Moreover,inanothermeta-analysis,PDE5-Isweremore effective in association with ABs, improving IPSS (mean difference –1.8), IIEF-5 score (meandifference +3.6), and Qmax (mean difference +1.5ml/s), when compared with PDE5-Is alone, which improved IPSS and IIEF scores but notQmax[16].

However, Dong et al [25] concluded that even after poolingfourdoses(2.5,5,10,and20mg),tadalafilfailed toproduceasignificantoutcomeinQmax,whereas5mg/d tadalafil therapysignificantlyimprovedQmax(mean dif-ference =+0.63ml/s,p= 0.04).

Asexpected,onlypatients intheTADgroupretained the IIEF-5improvement when compared withthe TAM group (16.96 vs 12.48; p= 0.003). Interestingly, the impactoftadalafilonIIEF-5wasmorepronounced,even if notclinically significant, in combinationwith tamsu-losin (+6.28 vs +4.64), suggesting a possible synergism betweenthesedrugs.Indeed,apreviousprospective ran-domized study demonstrated that EF improved with tamsulosin (+39.28% [p< 0.05]), tadalafil (+45.96% [p< 0.05]), and tamsulosin and tadalafil combination (+60.23% [p< 0.05]), with a better improvement seen in combination therapy compared with single agent alone.However,inlinewithour findings,the impactof combination treatment on EF was significantly greater thantamsulosinalone(p< 0.05)butnotwhencompared withtadalafil (p= 0.125)[28].

Inourstudy,wedescribedforthefirsttimeurinaryand sexualoutcomesachievedwithin12wkoftamsulosinor tadalafilmonotherapyafteraprevious12wkof combina-tion therapy, to achieve a tailored therapy based on patients’ predominant symptoms and to reduce drugs’ intake.

Aspreviouslyreportedfor thecombinationtherapyof tamsulosinanddutasteride,thewithdrawaloftamsulosin after24wkofcombinationtherapyhadnosignificanteffect onurinaryoutcomes.Indeed,LUTSreliefwasmaintainedin themajorityofpatientsaftertamsulosinwasremovedfrom combination,andtheauthorsconcludedthatonlypatients withseveresymptomsmaybenefitfromlonger-term com-binationtherapy[29].

Evenifcombinationtherapywithtamsulosinand tada-lafil achievedbetterurinaryandsexualoutcomes, aftera further 12 wkof monotherapy, both drugs were able to preserve a significant recovery of urinary function from baseline.Nevertheless,onlypatientstreatedwithtadalafil showed a satisfying sexualfunction and abetter storage IPSSattheendofthetrial.

Dailydosesoftadalafil5mgandtamsulosin0.4mgwere welltolerated.Nopatientsdiscontinuedthestudybecause ofAEs.HeadachewasthemainAE,withahigherincidence in theTAM group(8%)ascompared withthe TADgroup (4%),suggestingthattheuseoftamsulosincanincreasethe riskofthisAE.

Strengthsofthestudyaretheprospectivenatureofthe trial and data collection together with the homogenous population.However,thisstudymayberestrictedbysome limitations.Becausethisstudywasobservational,itcould bepronetobiases.Moreover,prostatesizewasnot consid-eredasinclusion/exclusioncriteriaorasapotential deter-minantontheefficacyoftherapy.Long-termfollow-upis also needed to better evaluate the role of a switching approach versus a continuous treatment in terms of patients’complianceintermofsymptoms,EF,urinaryflow managementandcosts.

Table 4 –Summary of adverse events reported during the

treatmentperiod(24wk). Group TAD (n = 25), n (%) Group TAM (n = 25), n (%) AnyTEAEs 4(16) 5(20) SeriousAEs 0(0.0) 0(0.0) Intensity Mild 3(12) 3(12) Moderate 1(4) 2(8) Severe 0(0.0) 0(0.0) Headache 2(8) 2(8) Nasopharyngitis 0(0.0) 1(4) Backpain 1(4) 1(4) Dizziness 0(0.0) 0(0.0) Dyspepsia 1(4) 0(0.0) Ejaculatorydysfunction 0(0.0) 1(4)

5. Conclusion

For men with LUTS and ED, combined treatment with tamsulosinandtadalafiliswelltoleratedandeffective.After 3moofcombinationtherapyandconsequent discontinua-tionoftamsulosin,monotherapywithtadalafilwasableto furtherpreservetheimprovementofLUTSandEFalthough withaslightdecreaseofQmax.Thepossibilitytoswitchfrom a combination approach to a single-treatment strategy seems a feasibleoption to improve patients’ compliance andtobettertailorLUTStreatment.

Authorcontributions:MauroGaccihadfullaccesstoallthedatainthe

studyandtakes responsibilityfor the integrityof the dataandthe

accuracy of the data analysis.

Study concept and design: Gacci.

Acquisition of data: Frizzi.

Analysis and interpretation of data: Gacci.

Draftingofthemanuscript:Sebastianelli,Spatafora.

Criticalrevisionofthemanuscriptforimportantintellectualcontent:De

Nunzio, Vignozzi.

Statistical analysis: Sebastianelli.

Obtaining funding: None.

Administrative, technical, or material support: Saleh.

Supervision:Serni,Tubaro,Maggi.

Other:visualization:McVary,Kaplan,Gravas,Chapple.

Financial disclosures: Mauro Gacci certifiesthat all conflictsof interest,

includingspecificfinancialinterestsandrelationshipsandaffiliations

relevanttothesubjectmatterormaterialsdiscussedinthemanuscript

(eg, employment/af_filiation,grants or funding, consultancies, honoraria,

stock ownership or options, expert testimony, royalties, or patents _filed,

received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

References

[1] GacciM,EardleyI,GiulianoF,etal.Criticalanalysisofthe rela-tionship betweensexual dysfunctions andlower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2011;60:809_–25.

[2] DeNunzioC,RoehrbornCG,AnderssonKE,etal.Erectiledysfunction andlowerurinarytractsymptoms.EurUrolFocus2017;3:352–63.

[3] NIHConsensusConference.Impotence.NIHconsensus develop-mentpanelonimpotence.JAMA1993;270:83–90.

[4] ShiriR,HakkinenJT,HakamaM,etal.Effectoflowerurinarytract symptoms on the incidence of erectile dysfunction. J Urol 2005;174:205_–9.

[5] AndersonKE, deGroat WC,McVAry KT, etal. Tadalafilfor the treatmentoflowerurinarytractsymptomssecondarytobenign prostatic hyperplasia: pathophysiology and mechanism(s) of action.NeurourolUrodyn2011;30:292–301.

[6] GacciM,CoronaG,VignozziL,etal.Metabolicsyndromeandbenign prostaticenlargement:asystematicreviewandmeta-analysis.BJU Int2015;115:24–31.

[7] VignozziL,RastrelliG,CoronaG,etal.Benignprostatichyperplasia: anewmetabolicdisease?JEndocrinolInvest2014;37:313–22.

[8]Vignozzi L,Gacci M, Maggi M.Lower urinary tract symptoms, benignprostatichyperplasiaandmetabolicsyndrome.NatRevUrol 2016;13:108–19.

[9]Mirone V, Sessa A, Giuliano F, et al. Current benign prostatic hyperplasiatreatment:impactonsexualfunctionandmanagement ofrelatedsexualadverseevents.IntJClinPract2011;65:1005_–13.

[10] GravasS,BachT,DrakeM,etal.Treatmentofnon-neurogenicmale LUTS2017.EuropeanAssociation ofUrology.http://uroweb.org/ guideline/treatment-of-non-neurogenic-male-luts/.

[11] Madersbacher S, Marszalek M,Lackner J, et al. The long term outcomeofmedicaltherapyforBPH.EurUrol2007;51:1522_–33.

[12] GiulianoF,ÜckertS,MaggiM,etal.Themechanismofactionof phosphodiesterase type 5 inhibitors inthe treatment oflower urinarytractsymptoms relatedto benignprostatichyperplasia. EurUrol2013;63:506–16.

[13] MorelliA,SarchielliE,ComeglioP,etal.Phosphodiesterasetype 5expressioninhumanandratlowerurinarytracttissuesandthe effectoftadala_filonprostateglandoxygenationinspontaneously hypertensiverats.JSexMed2011;8:2746–60.

[14] VignozziL,GacciM,CellaiI,etal.PDE5inhibitorsbluntin flamma-tioninhuman BPH:apotentialmechanism ofactionfor PDE5 inhibitorsinLUTS.Prostate2013;73:1391–402.

[15] MorelliA, Comeglio P,Filippi S, etal. Mechanism of actionof phosphodiesterasetype5inhibitioninmetabolic syndrome-asso-ciatedprostatealterations:anexperimentalstudyinthe rabbit. Prostate2013;73:428–41.

[16] GacciM,CoronaG,SalviM,etal.Asystematicreviewand meta-analysisontheuseofphosphodiesterase5inhibitorsaloneorin combinationwithalpha-blockersforlowerurinarytractsymptoms duetobenignprostatichyperplasia.EurUrol2012;61:994_–1003.

[17] SeratiM,AnderssonKE,DmochowskiR,etal.Systematicreviewof combinationdrugtherapyfornon-neurogeniclowerurinarytract symptoms.EurUrol2019;75:129–68.

[18]Barry MJ, Fowler J,O’LearyMP, etal. The American Urological Associationsymptomindexforbenignprostatichyperplasia.JUrol 1992;148:1549_–57.

[19] RosenRC,RileyA,WagnerG,etal.TheInternationalIndexofErectile Function(IIEF):amultidimensionalscaleforassessmentoferectile dysfunction.Urology1997;49:822–30.

[20] SebastianelliA,SpataforaP,FrizziJ,etal.Tadalafil5mgaloneorin combinationwithtamsulosin0.4mgforthemanagementofmen with lower urinary tract symptoms and erectile dysfunction: resultsofaprospectiveobservationaltrial.JClinMed2019;8:E1126.

[21] GacciM,AnderssonKE,ChappleC,etal.Latestevidenceontheuse ofphosphodiesterasetype5inhibitorsforthetreatmentoflower urinarytractsymptomssecondarytobenignprostatichyperplasia. EurUrol2016;70:124–33.

[22] MatsukawaY,TakaiS,MajimaT,etal.Objectiveimpactsoftadalafil on storageand voidingfunction in malepatients with benign prostatichyperplasia:1-yearoutcomesfromaprospective urody-namicstudy.WorldJUrol2018;37:867–72.

[23] OelkeM,GiulianoF,MironeV,etal.Monotherapywithtadalafilor tamsulosinsimilarlyimprovedlowerurinarytractsymptoms sug-gestiveofbenignprostatichyperplasiainaninternational, random-ised, parallel, placebo-controlled clinical trial. Eur Urol 2012;61:917_–25.

[24] OgerS,Behr-RousselD,GornyD,etal.Combinationofdoxazosin andsildenafilexertsanadditiverelaxingeffectcomparedwitheach compoundaloneonhumancavernosalandprostatictissue.JSex Med2009;6:836–47.

[25] DongY,HaoL,ShiZ.Ef_ficacyandsafetyoftadala_filmonotherapyfor lowerurinarytractsymptomssecondarytobenignprostatic hyper-plasia:ameta-analysis.UrolInt2013;91:10–8.

[26] UrakamiS,OgawaK,OkaS,etal.Effectoftadalafiladd-ontherapyin patientswithpersistantstoragesymptomsrefractorytoa1 -adre-noceptorantagonistmonotherapyforbenignprostatichyperplasia: arandomizedpilottrialcomparingtadalafilandsolifenacin.Low UrinTractSymptoms2019;11:109_–14.

[27] LaydnerHK, Oliveita P, Oliveira CP, et al. Phosphodiesterase 5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review. BJU Int 2011;107:1104–9.

[28] SinghDV,MeteUK,MandalAK,etal.Acomparativerandomized prospectivestudytoevaluateefficacyandsafetyofcombinationof tamsulosinandtadalafilvs.tamsulosinortadalafilaloneinpatients withlowerurinarytractsymptomsduetobenignprostatic hyper-plasia.JSexMed2014;11:187_–96.

[29] BarkinJ,GuimarãesM,JacobiG,etal.Alpha-blockertherapycanbe withdrawninthemajorityofmenfollowinginitialcombination therapywiththedual5alpha-reductaseinhibitordutasteride.Eur Urol2003;44:461–6.