Scuola di Specializzazione in Malae dell’Apparato ... · Dire8ore Prof. Massimo Volpe Facoltà di...

ScuoladiSpecializzazioneinMala/edell’ApparatoCardiovascolareDire8oreProf.MassimoVolpeFacoltàdiMedicinaePsicologia,UniversitàdiRomaSapienzaAnnoAccademico2014-2015Dr.LucaR.Limite

Proge8oFormazioneAvanzatainCardiologianelWeb2015ScuoladiSpecializzazioneinMala/edell’ApparatoCardiovascolare

Dire8ore:Prof.MassimoVolpe

E-mail:[email protected]

Coordinatore:Dr.GiulianoTocciE-mail:[email protected]

BACKGROUND:Resistanthypertension

•  SubopSmalbloodpressurecontroldespitetreatmentwithmaximaltolerateddosesof3drugs

•  ~10%ofhypertensivepaSents,equaSngto~100millionpeopleglobally

•  Thefirst3BP-loweringmedicaSonsshouldusuallybeanACE-inhibitororARB+CCB+Thiazide-likeDiureSc,i.e.A+C+D

Mya8A,etal.BMJ2012;NICEhypertensionguidelines2011

BACKGROUND::NICEguidelines

NICEhypertensionguidelines;availableat:h8p://pathways.nice.org.uk/(accessedon11/2/2015)

BACKGROUND:drugtherapy

•  Meta-analysison1204pts•  3smallRCTs(combined134paSents)aswellasopen/

observaSonalstudies•  Spironolactone(meandose~25mgdaily)versus

placebo•  NoRCTsdirectlycomparingspironolactonewithother

BP-loweringdrugs

DahalK,etal.AmJHypertens,2015

DahalK,etal.AmJHypertens,2015

BACKGROUND:drugtherapy

436pz335pz

WilliamsB,etal.BMJOpen,2015

Studydesign

Endpoints

HierarchicalPrimaryEnd-point

i.DifferenceinaveragehomesystolicBP(HSBP)betweenspironolactoneandplacebo

followed,ifsignificantby

ii.HSBPdifferencebetweenspironolactoneandtheaverageoftheothertwoacSvedrugs(bisoprololanddoxazosin)

followed,ifsignificantby

iii.HSBPdifferencebetweenspironolactoneandeachoftheothertwoacSvedrugs

WilliamsB,etal.Lancet,2015

Endpoints

SecondaryOutcomeMeasures

SeatedclinicBPresponsestoeachtreatment

Bloodpressurecontrolrateswitheachtreatment(averageHSBP<135mmHg)

Safetyandadverseevents

Whetherbaselineplasmarenin(whilstontreatmentwithA+C+D)predictedthebestdrugforindividualpaSents



BASELINEPATIENTSDEMOGRAPHICS(N=335)

Mean(SD)orN(%)

Age(yrs) 61.4(9.6)

Male 230(68.7%)

Weight(kg) 93.5(18.1)

Smoker 26(7.8%)

HomeBP(mmHg) Systolic 147.6(13.2)

Diastolic 84.2(10.9)

ClinicBP(mmHg) Systolic 157(14.3)

Diastolic 90.0(11.5)

Bloodelectrolytes Sodium(mmol/l) 140(3.0)

Potassium(mmol/l) 4.1(0.47)

eGFR(ml/min) 91.1(26.8)

DiabeSc 46(13.7%)

Treatments HSBP(mmHg) Changefrombaseline

Spironolactone 133.5(132.3to134.8) -14.4(-15.6to-13.1)

Doxazosin 138.8(137.6to140.1) -9.1(-10.3to-7.8)

Bisoprolol 139.5(138.2to140.8) -8.4(-9.7to-7.1)

Placebo 143.7(142.5to145.0) -4.2(-5.4to-2.9)

Comparators(n=314) HSBPdifference(mmHg) pvalue

SpironolactonevsPlacebo -10.2(-11.7to-8.74) p<0.0001

SpironolactonevsmeanBisoprolol/Doxazosin

-5.64(-6.91to-4.36) p<0.0001

SpironolactonevsDoxazosin -5.3(-6.77to-3.83) p<0.0001

SpironolactonevsBisoprolol -5.98(-7.45to-4.51) p<0.0001


RESULTS:HSBPatthefinalvisitofeachcycle(12weeks)

Treatments HSBP(mmHg) Changefrombaseline

Spironolactone 136.5(134.4–138.7) -20.7(-22.9to-18.6)

Doxazisin 141.0(138.8–143.1) -16.3(-18.5to-14.2)

Bisoprolol 141.0(138.8–143.2) -16.3(-18.4to-14.1)

Placebo 146.5(144.3–148.6) -10.8(-13.0to-8.7)

Comparators(n=314) Clinicsystolicbloodpressuredifference(mmHg)

pvalue

SpironolactonevsPlacebo -9.92(-11.3-8.59) p<0.0001

SpironolactonevsmeanBisoprolol/Doxazosin

-4.44(-5.59-3.28) p<0.0001

SpironolactonevsDoxazosin -4.42(-5.75-3.09) p<0.0001

SpironolactonevsBisoprolol -4.45(-5.80-3.11) p<0.0001


RESULTS:Clinicsystolicbloodpressure

HighervsLowerdose HSBP(mmHg) Pvalue

Spironolactone -3.86(-5.28to-2.45) p<0.001

Doxazosin -0.88(-2.32to0.56) 0.231

Bisoprolol -1.49(-2.94to-0.04) 0.043

Placebo -0.68(-2.1to0.75) 0.350

Difference inmean HSBP aqer treatment with the lower dose (week 6) versus thehigherdoses(week12)ofeachtreatment


RESULTS:doseresponse

RESULTS:BPcontrolratesHomesystolicbloodpressure(mmHg)

PaSents Mettarget LeastSquaresesSmates

OddsraSo Pvalue

Baseline Final n. n.(%)

Spironolactone 148.3 133.9 282 163(57.8%) 58.0(52.0-63.7)

<0.001

Doxazosina 147.8 138.9 276 115(41.7%) 41.5(35.8-46.5)

0.52(0.37-0.73)

<0.001

Bisoprololo 147.7

139.6 280 122(43.6%) 43.3(37.5-49.2)

0.55(0.39-0.78)

<0.001

Placebo 147.8 143.5 270 66(24.4%) 23.9(19.1-29.4)

0.23(0.16-0.33)

<0.001



AdverseEvents

Bisoprolol Spironolactone Doxazosin Placebo pvalue

Seriousadverseevents

8(2.6%)

7(2.3%)

5(1,7%)

5(1.7%)

0.831

Anyadverseevent

68(11.3%)

67(10.4%)

58(10.1%)

42(9.1%)

0.711

Withdrawalforadverseevents

2(2.9%)

3(3.4%)

8(10.0%)

2(2.6%)

0.084


Baseline Followup Change pvalue

Sodium(mmol/L)

Spironolactone 139·74 137·84 -1·91 <0·001

Doxazosin 139·37 139·30 -0·07 0·840

Bisoprolol 139·96 139·78 -0·17 0·608

Placebo 139·14 139·25 0·11 0·745

Potassium(mmol/L)

Spironolactone 4·06 4·49 0·43 <0·001

Doxazosin 4·08 4·16 0·08 0·127

Bisoprolol 4·11 4·26 0·15 0·007

Placebo 4·05 4·09 0·03 0·410

eGFR(ml/min)

Spironolactone 93·20 83·18 -10·02 0·004

Doxazosin 92·70 85·38 -7·32 0·023

Bisoprolol 92·40 86·35 -6·05 0·006

Placebo 92·52 92·67 0·15 0·923


Sodium(mmol/L)

Spironolactone 139·74 137·84 -1·91 <0·001

Doxazosin 139·37 139·30 -0·07 0·840

Bisoprolol 139·96 139·78 -0·17 0·608

Placebo 139·14 139·25 0·11 0·745

Potassium(mmol/L)

Spironolactone 4·06 4·49 0·43 <0·001

Doxazosin 4·08 4·16 0·08 0·127

Bisoprolol 4·11 4·26 0·15 0·007

Placebo 4·05 4·09 0·03 0·410

eGFR(ml/min)

Spironolactone 93·20 83·18 -10·02 0·004

Doxazosin 92·70 85·38 -7·32 0·023

Bisoprolol 92·40 86·35 -6·05 0·006

Placebo 92·52 92·67 0·15 0·923



Sodium(mmol/L)

Spironolactone 139·74 137·84 -1·91 <0·001

Doxazosin 139·37 139·30 -0·07 0·840

Bisoprolol 139·96 139·78 -0·17 0·608

Placebo 139·14 139·25 0·11 0·745

Potassium(mmol/L)

Spironolactone 4·06 4·49 0·43 <0·001

Doxazosin 4·08 4·16 0·08 0·127

Bisoprolol 4·11 4·26 0·15 0·007

Placebo 4·05 4·09 0·03 0·410

eGFR(ml/min)

Spironolactone 93·20 83·18 -10·02 0·004

Doxazosin 92·70 85·38 -7·32 0·023

Bisoprolol 92·40 86·35 -6·05 0·006

Placebo 92·52 92·67 0·15 0·923

Only6of285ptsexposedtoMRAdevelopedaserumpotassium>6mmol/l


ReninProfileversusDrugResponse


ReninProfileversusDrugResponse


•  SpironolactonehasbeenshowntobethemosteffecSvedrugtreatmentforresistanthypertension,controllingBPinalmost60%ofpaSents

•  Spironolactonewaswelltolerated•  Thedose-dependentresponsetospironolactonewas

inverselyrelatedtoplasmarenin•  Thesuperiorityofspironolactonesupportsaprimary

roleofsodiumretenSoninresistanthypertension

SUMMARY


•  Resistanthypertensionisasodiumretainingstate,characterizedbyaninappropriatelylowplasmareninleveldespitetreatmentwithA+C+D

•  Undetectedaldosteroneproducingadenomas?•  FurtherdiureSctherapywithspironolactoneismore

effecSveatloweringBPthanalternaSvetreatments,targeSngdifferentmechanisms

HYPOTHESIS:asodiumretainingstate?


•  Onlywhitecaucasians•  HealthypaSents•  TooshorttreatmentduraSontoassesstheoccurrence

ofsideeffects(i.e.gynecomasSa~6%inlonger-termstudies)

•  Long-termcardiovascularandrenaloutcomes?•  Nodataonserumaldosteroneorcomparisonwithan

increaseindoseofthebackgrounddiureSc

SternlichtHetal.Lancet2015

CRITICISMS

ScuoladiSpecializzazioneinMala/edell’ApparatoCardiovascolareDire8oreProf.MassimoVolpeFacoltàdiMedicinaePsicologia,UniversitàdiRomaSapienzaAnnoAccademico2014-2015Dr.LucaR.Limite

Proge8oFormazioneAvanzatainCardiologianelWeb2014ScuoladiSpecializzazioneinMala/edell’ApparatoCardiovascolare

Dire8ore:Prof.MassimoVolpe

E-mail:[email protected]

Coordinatore:Dr.GiulianoTocciE-mail:[email protected]

GrazieperlaVostraA8enzione

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