terapia antipiastrinica in casi specifici: anziani, dm ... · mi/stroke/cv death within 30 days...

TERAPIAANTIPIASTRINICAINCASISPECIFICI:ANZIANI,DM,IRC,NONRIVASCOLARIZZATI

Dr.ssaBuscemiMarialauraDivisionediCardiologiaAziendaOspedalieraSS.AntonioeBiagioeC.Arrigo

CASISPECIFICI?§  Anziani(>75aa)rappresentanoil25%dellapopolazioneconSCA

§  Il30-40%deipazienGricoveraGperSCApresentanoIRCedil20-30%èdiabeGco

§  PazienGnonrivascolarizzaG:40%dellapopolazioneconSCA

Ø OgnigiornocitroviamoadaffrontaredecisioniterapeuGcheinquestedelicatecategoriedipazienG

TERAPIAANTIPIASTRINICAINCASISPECIFICI Dr.ssaBuscemiMarialaura

ANALOGIE/DIFFERENZETRAIBLOCCANTIRECETTORIALIDELL’ADPRACCOMANDATI

CURE:DISEGNODELLOSTUDIO

Clopidogrel 75mg q.d. + ASA 75-325

mg q.d.* (6259 patients)

Placebo + ASA 75-325 mg q.d.* (6303 patients)

Patients with Acute Coronary

Syndrome

(unstable angina or non-ST-segment

elevation MI)

R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

3 months ≤ double-blind treatment ≤ 12 months

Clopidogrel 300 mg loading dose

PRIMARYENDPOINT-MI/STROKE/CVDEATH

Clopidogrel + ASA*

Placebo + ASA*

Months of Follow-Up

20% RRR P < 0.001

N = 12,562

* In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

MI/STROKE/CVDEATHWITHIN30DAYS

Clopidogrel + ASA*

10 20 30

Placebo + ASA*

Days of Follow-Up

21% RRR P = 0.003

N = 12,562

* In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Placebo + ASA

N = 6303

Clopidogrel + ASA

N = 6259 End Point

Majorbleeding 2.7% 3.7%

Life-threateningbleeding 1.8% 2.2%

Non-life-threateningbleeding 0.9% 1.5%

Minorbleeding 2.4% 5.1%

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

BLEEDINGRESULTS

CLOPIDOGREL:VARIABILITA’DIRISPOSTA

Serebruany,JACC2005

NUOVIANTIAGGREGANTI

%&'$()*+,-.*&-&*$(/&)*0$

TRITON-TIMI38:studydesignandprimaryefficacyendpoints

& Planned PCI

Primaryefficacyendpoint:acompositeoftherateofdeathfromcardiovascularcauses,nonfatalMI,ornonfatalstroke

UA/NSTEMI (TIMI Risk Score ≥ 3)

STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days)

Prasugrel60mgLD/10mgMD

Clopidogrel300mgLD/75mgMD

Keysecondaryendpointsat30and90daysincludedprimaryefficacyendpointandacompositeoftherateofdeathfromcardiovascularcauses,nonfatalMI,orUTVR

14.5monthactualmedian

12.0monthplannedmedian

Double-blindtreatment6-15monthsplannedfollow-up

Keysafetyendpoint:non-CABGrelatedTIMIMajorBleeding

WivioeSDetal.NewEnglJMed2007;357:2001-2015WivioeSDetal.AmHeartJ2006;152:627-635

PRIMARYENDPOINTCVDEATH,MI,STROKE

0 30 60 90 180 270 360 450

HR 0.81 (0.73-0.90) P=0.0004

Prasugrel

Clopidogrel

HR 0.80 P=0.0003

HR 0.77 P=0.0001

12.1 (781)

9.9 (643)

NNT= 46

ITT=13,608 LTFU=14(0.1%)

STENTTHROMBOSIS(ARCDEFINITE+PROBABLE)

0 30 60 90 180 270 360 450

HR 0.48 P <0.0001

Prasugrel

Clopidogrel 2.4 (142)

NNT= 77

1.1 (68)

) AnyStentatIndexPCIN=12,844

TRITON-TIMI38:RATESOFKEYSTUDYENDPOINTS(ALLACS)

CABG=CoronaryArteryBypassGrahsurgery;CV=Cardiovascular;MI=MyocardialInfarcGon;TIMI=ThrombolysisInMyocardialInfarcGon

Prasugrel

Clopidogrel

WivioeSDetal.NewEnglJMed2007;357:2001-2015

00 30 60 90 180 270 360 450

Days After Randomization

1.8 (n=111)

2.4 (n=146)

Non-CABG TIMI Major Bleeds

CV Death, MI, Stroke

P=0.03

P<0.001 ↓138 events

↑ 35 events

12.1 (n=781)

9.9 (n=643)

Prasugrel

Clopidogrel

NETCLINICALBENEFITDEATH,MI,STROKE,MAJORBLEED(NONCABG)

0 30 60 90 180 270 360 450Days

HR 0.87 P=0.004

Prasugrel

Clopidogrel ITT=13,608

AllCauseMortalityClop3.2%Pras3.0%P=0.64

PLATOSTUDYDESIGN

Primaryendpoint:CVdeath+MI+Stroke

Primarysafetyendpoint:Totalmajorbleeding

6–12-monthexposure

Clopidogrel(n=9291)Ifpre-treated,noaddiGonalloadingdose;ifnaive,standard300mgloadingdose,

then75mgqdmaintenance;(addiGonal300mgallowedprePCI)

Ticagrelor(n=9333)180mgloadingdose,then90mgbidmaintenance;(addiGonal90mgpre-PCI)

NSTE-ACS(moderate-to-highrisk)STEMI(ifprimaryPCI)Clopidogrel-treatedor-naive;

randomisedwithin24hoursofindexevent(N=18,624)

PLATOMAINENDPOINTS

No. at risk

Clopidogrel

Ticagrelor 9,291

Months

4,147 8,219

0 2 4 6 8 10 12

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

WallenGnetal.,NewEngJMed.2009;361:1045–1057

0 2 4 6 8 10 12

Clopidogrel

Ticagrelor

HR 1.04 (95% CI 0.95–1.13), p=0.434

Months

Primary safety endpoint Primary efficacy endpoint

6,670 5,209

3,433 6,545

ALLCAUSEMORTALITY

1 2 3 4 5 6 7 8 9 10 11 12

4,201 4,005 3,962 3,876 3,150 2,413 1,993 4,229 4,029 3,989 3,912 3,195 2,471 1,980

Months

No. at risk Ticagrelor Clopidogrel

Clopidogrel

Ticagrelor

HR 0.82 (95% CI = 0.68–0.99), p=0.04

ANTIAGGREGANTINELNSTEMI

2014ESC/EACTSGuidelinesonmyocardialrevascularizaCon

ANTIAGGREGANTINELLOSTEMITRATTATOCONPCI

2014ESC/EACTSGuidelinesonmyocardialrevascularizaCon

QUALETERAPIAANTIPIASTRINICAORALENEIPAZIENTIANZIANI(>75ANNI)?

ANZIANI

§  Lelineeguidasonobasatesutrialcondomsumaschidi60anni.

§  UnaquotamaggioreecrescentedeinostripazienGsonodonnedioltre70anni

§  Bisognatenercontodelleeventualicomorbilità,condizioniassociate(fragilità,declinofunzionaleecogniGvoeladipendenzafisica)

ANZIANI§  PresentaproblemaGchespecifichedaconsiderare,

quali:Ø laridoeamassamagrachepuòcambiareilvolumedidistribuzionedifarmaciidrofilicielipofilici;

Ø ilrallentatotransitointesGnalechepuòcambiarel’assorbimentodeifarmaci;

Ø lapoliterapiachecreaproblemaGchediinterazionifarmacologiche;

Ø lecomorbilità,comeladisfunzionerenalechepuòdeterminarel’accumulodifarmacieliminaGperviarenale

QUALESTRATEGIAFARMACOLOGICANEIPAZIENTIANZIANI?

§  CURE:rispeeoaipazienGpiùgiovanilariduzionedelRRdell’incidenzadiendpointprimario(mortevascolare,infartomiocardicoedictus)èrisultataesserepiùaeenuatanell’anziano(13vs29%),anchesepoiciòsitraducevainunasimileriduzionedelrischioassoluto(2.0vs2.2%)

§  DiversistudiosservazionaliefarmacodinamicisuggerisconochetraipazienGanzianiaumentalaresistenzaalclopidogrel

TRITONTIMI38POST-HOCANALYSIS

BENEFICIOCLINICONETTO:SOTTOGRUPPIADELEVATORISCHIODISANGUINAMENTO

WivioeSetal.NEnglJMed2007:2001-15

PRASUGRELTRILOGYACS

TRILOGYACS

PLATOELDERLYPATIENTSUBGROUPANALYSIS:AGE,TREATMENTANDCVTHROMBOTICOUTCOMES

Events, n Ticagrelor, %

(n=9333) Clopidogrel, %

(n=9291) p for interaction

CV death, MI or stroke ≥75 years old <75 years old

All-cause mortality ≥75 years old <75 years old MI ≥75 years old <75 years old CV death ≥75 years old <75 years old Definite stent thrombosis ≥75 years old <75 years old

471 1399

17.2 8.6

18.3 10.4

293 608

9.8 3.6

12.4 4.8

241 864

9.3 5.4

9.4 6.6

242 549

8.1 3.3

10.3 4.2

1.8 1.3

2.1 1.9

Ticagrelor better Clopidogrel better

0.5 1.0 2.0 0.3 1.5

PLATOELDERLYPATIENTSUBGROUPANALYSIS:ASSOCIATIONOFAGEANDTREATMENTWITHCLINICALOUTCOMES

TheriskofbleedingeventsinbothyoungandelderlypaientsisconsistentwiththatobservedintheoverallPLATOtrial[WallenGn2009:I;Husted2011:F,K]

Nointeracionbetweenageandtreatmentwasobserved

Events, n Ticagrelor, %

(n=9333) Clopidogrel, %

(n=9291) p for interaction

Major bleeding ≥75 years old <75 years old

341 1545

14.2 11.2

13.5 10.8

Non-CABG-related major bleeding ≥75 years old <75 years old

183 482

8.3 3.9

7.1 3.2

CABG, coronary artery bypass graft; CI, confidence interval; HR, hazard ratio. Wallentin L, et al. N Engl J Med 2009;361:1045–1057;

Husted S, et al. J Am Coll Cardiol 2011;57:E1099.

Ticagrelor better Clopidogrel better

1.0 2.0 0.5 1.5

…QUINDINELPZ>75ANNI

•  Ticagrelor>(o=)Clopidogrel•  Prasugrel5mg=Clopidogrel•  Prasugrel10mg<Clopidogrel

QUALETERAPIAANTIPIASTRINICAORALENEIPAZIENTIDIABETICI?

DIABETICI

§  pazienGaffemdaSCAdiabeGcihannotassodimortalitàpiùelevatorispeeoainondiabeGci

§  l’alterazionedelmetabolismoglucidico,l’insufficienzadell’azioneinsulinica,molteplicicondizionimetabolicheedaltreanomaliecellulari(es.aumentatoturnoverpiastrinico,upregulaGondelsegnaleP2Y12estressossidaGvo)provocanoun’intensaamvazionedell’aggregazionepiastrinica

§  resistenzaaifarmacianGaggreganGpiastrinicialmeno4-5voltemaggiorerispeeoainondiabeGci

TRITON-TIMI38.PAZIENTIDIABETICI.N=3146

0 30 60 90 180 270 360 450

HR 0.70 P<0.001

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 21

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6 2.5

SOTTOSTUDIODELPLATO.PAZIENTIDIABETICI

Ticagrelor Clopidogrel

N. a rischio 2326 2113 2045 1959 1593 1199 953 2336 2084 2041 1968 1604 1225 975 6999 6507 6407 6252 5143 3955 3191 6952 6434 6318 6153 5044 3869 3097

Incidenza cumulativa dell’endpoint primario (morte CV, IM, ictus)

t prim

60 120 240 300 Giorni dalla randomizzazione

360 180

No diabete Ticagrelor Clopidogrel

Diabete

Fig. 1A e Tab. 4, Rif. g13

Non diabetici: HR: 0,83; IC 95%: 0,74-0,93 (RRR=17%)

Ticagrelor:180mg(dosedacarico),quindi90mgBIDClopidogrel:300-600mg(dosedacarico),quindi75mgOD

Dosiaddizionali:300mgdiclopidogrelprimadellaPCI

Diabetici: HR: 0,88; IC 95%: 0,76-1,03 (RRR=12%)

HbA1c ≥ 6,0% HbA1c < 6,0%

p=0,24

RRR 7%

RRR 20%

HbA1c < 6,0%: ticagrelor 8,2%, clopidogrel 9,0%; HR: 0,93; IC 95%: 0,79-1,09 HbA1c ≥ 6,0%: ticagrelor 11,4%, clopidogrel 14,2%; HR: 0,80; IC 95%: 0,70-0,91

8,4 10,2

…QUINDIINPZDIABETICI

§  Ticagrelor>Clopidogrel§  Prasugrel>>Clopidogrel

QUALETERAPIAANTIPIASTRINICAORALENEIPAZIENTICONINSUFFICIENZARENALE?

INSUFFICIENZARENALECRONICA

§  PazienGconSCAeinsufficienzarenalepresentano:

Ø piùaltamortalità,rischioischemicoerischioemorragicoetalerischioaumentainmanieraesponenzialeneipazienGconfiltratoglomerulare≤30ml/min/1.73m2

Ø rischioditrombosidistentdocumentataoprobabilecirca3.5voltesuperioreallostandard

ANTIAGGREGANTIEINSUFFICIENZARENALE

MontalescotCirculaGonsept142010

…QUINDIINPZCONINSUFFICIENZARENALE

§  Ticagrelor>>Clopidogrel§  Prasugrel>=Clopidogrel

QUALETERAPIAANTIPIASTRINICANEIPAZIENTINONRIVASCOLARIZZATI?

NONRIVASCOLARIZZATI§  RecenGregistriinternazionalihannodocumentatoche

circail40%deipazienGricoveraGcondiagnosidiSCAricevonountraeamentoconservaGvo

§  duepopolazionidisGnte:Ø pazienGche,acausadelRelevato(pazienGfragiliconmulGplecomorbilità)otroppobasso,nonsononeanchesoeoposGadesamecoronarografico;

Ø pazienGchedopolacoronarografianonvengonorivascolarizzaGperillororischioanatomicotroppobasso(coronaropaGasubcriGcaomalamaostrumvadiunvasosecondario)o,incasipiùrari,perlapresenzadiunacoronaropaGaostrumvatalmenteseveraedestesadaesseregiudicatanonrivascolarizzabile. "

ComorbiditiesPatient refusalRevasc.unsuitableDNR statusAdvanced ageActive bleeding Other

17% 16%

ReasonsforcontraindicaionstocardiaccatheterizaionintheCRUSADERegistry

Comorbidiies

(CV death, MI,stroke)

PRASUGRELTRILOGYACS

HR0.91(95%CI,0.79to1.05)p=0.21 HR0.93(95%CI,0.75to1.15)

non inv

HR 0,85 (0,73-1,00), p = 0,045 HR 0,75 (0,61-0,93), p = 0,010

non inv

HR 1,17 (0,98-1,39), p = 0,079

…NELL’UA/NSTEMIESTRATEGIACONSERVATIVA

§  Ticagrelor>Clopidogrel§  Prasugrel<o=Clopidogrel

SCELTAANTIAGGREGANTESECONDOG.L.ESC/AHA/ACC

*Prasugrelinassenzacontroindicazioni(stroke/TIA) S.D.WivioeLANCETMarch2015

CONCLUSIONI:comemicomportonellapraicaclinica?

Clopidogrel Prasugrel Ticagrelor

STEMIePCIprimaria + ++ ++UA/NSTEMIePCI + ++ ++UA/NSTEMIestrategiaconservaGva + - ++>75anni + + +(+)DiabeGci + ++ ++PzconTIA/stroke + - +Insufficienzarenale<60ml/min + + ++

GRAZIEDELL’ATTENZIONE

SOTTOANALISIDELLOSTUDIOTRITON-TIMI38EVENTICLINICICORRELATIALLOSTATODID.M.

WivioeSD,NEnglJMed2007;357(20):2001-15

Ratesofcardiovasculardeath,nonfatalmyocardialreinfarcion,nonfatalstroke,andmajorbleedingwithinthefollow-upperiodinpaientsaged>75yearsenrolledinthePLATO5andTRITON-TIMI386trials.

JukemaJW,CurrentMedicalResearch&Opinion Vol.28,No.2,2012,203–211,

CONCLUSIONI:RUOLONUOVIANTIAGGREGANTI

TICAGRELOR PRASUGRELRIVASCOLARIZZAZIONE

TERAPIAMEDICADIABETICI

PRETRATTAMENTOINSUFF.RENALE

ANZIANIPESO

STROKE/TIAISCHEMICOTAO/NAOMORTALITA’

SITID’AZIONEDELTRATTAMENTOANTIPIASTRINICOYousufO,BhaeDL.NatRevCardiol2011:doi:10.1038/nrcardio.2011.96

YousufO,BhaeDL.NatRevCardiol2011:doi:10.1038/nrcardio.2011.96TargetedanGplatelettherapies

COMPARINGMEANAGESOFITALIANACSREGISTRIESANDGUIDELINE-BUILDINGTRIALS

Eur Heart J Acute CV Care

NSTEACS STEMI

BLITZ 4

Eur Heart J Acute CV Care

BLITZ 4

62 62 62

RITA III

Lancet 2002

TIMI 18

NEJM 2001

ICTUS NEJM 2005

TRITON Lancet 2009

HORIZONS NEJM 2008

PLATO Circulation

SavonieoS.RevEspCardiol2014;67:564

COURAGEmeanage62SINTAXmeanage65BESTmeanage64

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