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

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*

3 6 9

Placebo + ASA*

Months of Follow-Up

11.4%

9.3%

20% RRR P < 0.001

N = 12,562

0 12

* 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

0

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$

!"##$

!"#!$

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

TRITON-TIMI38:studydesignandprimaryefficacyendpoints


& Planned PCI

ASA

ASA

Primaryefficacyendpoint:acompositeoftherateofdeathfromcardiovascularcauses,nonfatalMI,ornonfatalstroke

=

UA/NSTEMI (TIMI Risk Score ≥ 3)

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

R

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

5

10

15

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

Days

Prim

ary

End

poin

t (%

)

12.1 (781)

9.9 (643)

NNT= 46

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

STENTTHROMBOSIS(ARCDEFINITE+PROBABLE)


0

1

2

0 30 60 90 180 270 360 450

HR 0.48 P <0.0001

Prasugrel

Clopidogrel 2.4 (142)

NNT= 77

1.1 (68)

Days

End

poin

t (%

) AnyStentatIndexPCIN=12,844

TRITON-TIMI38:RATESOFKEYSTUDYENDPOINTS(ALLACS)


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

Prasugrel

Clopidogrel

WivioeSDetal.NewEnglJMed2007;357:2001-2015

5

10

15

00 30 60 90 180 270 360 450

Days After Randomization

End

Poi

nt (%

)

120

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

5

10

15

0 30 60 90 180 270 360 450Days

HR 0.87 P=0.004

13.9

12.2

Prasugrel

Clopidogrel ITT=13,608

AllCauseMortalityClop3.2%Pras3.0%P=0.64

End

Poi

nt (%

)

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

9,333

8,521

8,628

8,362

8,460

8,124

Months

6,743

6,743

5,096

5,161

4,047

4,147 8,219

0 2 4 6 8 10 12

12

11

10

9

8

7

6

5

4

3

2

1

0

13

K-M

est

imat

ed ra

te (

% p

er y

ear)

9.8

11.7

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

10

5

0

15

Clopidogrel

Ticagrelor

11.20

11.58

HR 1.04 (95% CI 0.95–1.13), p=0.434

K-M

est

imat

ed ra

te (

% p

er y

ear)

Months

Primary safety endpoint Primary efficacy endpoint

9,186

9,235

7,305

7,246

6,930

6,826

6,670 5,209

5,129

3,841

3,783

3,479

3,433 6,545

ALLCAUSEMORTALITY


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

7

6

5

4

3

2

1

0

K-M

est

imat

ed ra

te (%

per

yea

r)

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

4.9

6.0

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

25

141

1.8 1.3

2.1 1.9

Ticagrelor better Clopidogrel better

0.22

0.78

0.25

0.90

0.94

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

1.00

0.78

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

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70 P<0.001

Days

End

poin

t (%

)

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 21

17.0

12.2

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)

End

poin

t prim

ario

0 0

10

5

60 120 240 300 Giorni dalla randomizzazione

20

15

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

16,2

8,4 10,2

14,1

…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

20%

18%

17% 16%

11%

4%

14%

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

2012

80-

75-

70-

65-

60-

55-

NSTEACS STEMI

74 68

BLITZ 4

women

men

Eur Heart J Acute CV Care

2012

68 63

BLITZ 4

women

men

62 62 62

RITA III

Lancet 2002

TIMI 18

NEJM 2001

ICTUS NEJM 2005

60 59

TRITON Lancet 2009

HORIZONS NEJM 2008

PLATO Circulation

2011

59

years

SavonieoS.RevEspCardiol2014;67:564

COURAGEmeanage62SINTAXmeanage65BESTmeanage64

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

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