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RivascolarizzazioneRivascolarizzazione miocardica nelle

SCASCA

Angelo Sante Bongo

Angelo Sante Bongo

Trattamento antitrombotico inTrattamento antitrombotico in corso di IMAcorso di IMA

RischioRischio

trombotico

Rischio emorragico

Angelo Sante Bongo

Farmaci antitrombotici nelle SCAFarmaci antitrombotici nelle SCAFarmaci antitrombotici nelle SCAFarmaci antitrombotici nelle SCA

EnoxaparinFundaparinuxBivalirudin

EnoxaparinFundaparinuxBivalirudin

ASAASAASAASA +UFH+UFH +Thyenop.+Thyenop. +IIb/IIIa inhib

+IIb/IIIa inhib

BivalirudinBivalirudin

inhib.inhib.

berlin

1960 2007

Angelo Sante Bongo

Landmark Practice Advances in Acute Coronary Syndromes

STEMISTEMI

y y

VIENNA REGISTRYVIENNA REGISTRY

SKSK SK+SK+ASPIRINASPIRIN

rr--tPAtPA TNKTNK

PRIMARY PCIPRIMARY PCI ABCIXIMABABCIXIMAB

CLOPIDOGRELCLOPIDOGREL

BIVALIRUDINBIVALIRUDIN

PrePre--H lysisH lysisMorrisonMorrison

REACTREACT CARESSCARESS

ASPIRIN +ASPIRIN + CLOPIDOGRELCLOPIDOGREL ABCIXIMABABCIXIMAB

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008

SSHEPARINHEPARIN19831983--’88’88 UPSTREAMUPSTREAM

GP IIb/IIIaGP IIb/IIIa

ABCIXIMABABCIXIMABIN CATH LABIN CATH LAB

FONDAPARINUXFONDAPARINUX

NSTENSTE--ACSACSTROPONINTROPONIN

EARLY INVASIVEEARLY INVASIVEBIVALIRUDINBIVALIRUDIN

ENOXAPARINENOXAPARIN

Angelo Sante Bongo

TROPONINTROPONIN

The 3 Most Important Advances inThe 3 Most Important Advances inThe 3 Most Important Advances in Antiplatelet Therapy for ACS

The 3 Most Important Advances in Antiplatelet Therapy for ACS

A i i• Aspirin

• ADP antagonistsg

• Platelet GP IIb/IIIa receptor antagonists

Angelo Sante Bongo

Angelo Sante BongoMeadows TA, Bhatt DL. Meadows TA, Bhatt DL. Circ ResCirc Res. 2007;100:1261. 2007;100:1261

ProPro--drugdrug NN

OO

OOOONN

OO OO CHCH33CHCH33CCCC

Prasugrel

SSCCHH33

CCOO

FFOO

SS ClCl

Clopidogrel

OO

85%85% Inactive Inactive MetabolitesMetabolites

OO OO CH3CHCH33CCCOO OO CH3CHCH33CCCOO OO CH3CHCH33CCCOO OO CH3CHCH33CCC

NNSS FF

OONN

SS ClCl

NNSS ClCl

NNSS ClCl

NNSS ClCl

OONN

SS

OO

ClCl

OO CH3CHCH33CCC

OOOONN

SS

OO

ClCl

OO CH3CHCH33CCC

NNSS

OO

ClCl

OO CH3CHCH33CCC

HOOCHOOC* HS* HS

NN

OO

FFHOOCHOOC NN

OO OCH3OCH3

HOOCHOOC NN

OO

HOOCHOOC NN

OO OCH3OCH3 Active Active metabolitemetabolite

Angelo Sante Bongo

* HS* HS FF* HS* HS ClCl* HS* HS ClCl* HS* HS ClClmetabolitemetabolite

ADP-receptor antagonists – major drawbacksdrawbacks

Clopidogrel is only slightly more effective than aspirin

As with aspirin clopidogrel binds irreversibly toAs with aspirin, clopidogrel binds irreversibly to platelets

In some patients there is resistance to clopidogrel treatmenttreatment

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GPIIb/IIIa-receptor antagonists –major drawbacksmajor drawbacks

Can only be administered by intravenous injection or infusion and are complicated to manufacture

OOral drugs have been investigated but were not effective and have therefore not reached the

k tmarket

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Antiplatelet Therapy in ACS1 08 ASA

ASA + Clopidogrel ASA +ASA +ASA + Clopidogrel ASA + ASA + PrasugrelPrasugrel

- 22% Reductionin

- 20%

- 19%

inIschemicEvents

+ 60% + 38% + 32%

Increasein

0

Placebo APTC CURE TRITON-TIMI 38Si l D lD l

+ 60% + 38% + 32%Major

Bleeds

Angelo Sante Bongo

Single Antiplatelet Rx

Dual Dual Antiplatelet RxAntiplatelet Rx Higher Higher

IPAIPA

What is the Problem? We Always Mix Antiplatelet Agents

ThromboxaneThromboxane5HT5HT 5HT5HT

C l tiC l ti C llC ll

ASPIRINASPIRIN

xTICLOPIDINETICLOPIDINECLOPIDOGRELCLOPIDOGRELPRASUGRELPRASUGREL

ThrombinThrombin

AA22 ADPADP ADPADPADPADP

P2Y15HT2A

TPa

CoagulationCoagulation

GPVI

CollagenCollagen

ATPATPATPATP

P2X

x PRASUGRELPRASUGREL

PAR1

PAR4

Densegranule

P2X1 ACTIVE ACTIVE METABOLITEMETABOLITE

x AZD6140 AZD6140 P2Y12PLATELETPLATELET

ACTIVATIONACTIVATION

granule

ThrombinThrombingenerationgeneration

x CANGRELORCANGRELOR

ShapeShapechangechange

AmplificationAmplificationAlpha

granule

aIIbb3

aIIbb3

FibrinogenFibrinogen aIIbb3

AggregationAggregationgranule

Coagulation factorsCoagulation factors

x

Angelo Sante Bongo

Coagulation factorsCoagulation factorsInflammatory mediatorsInflammatory mediators

GP IIb/IIIa ANTAGONISTSGP IIb/IIIa ANTAGONISTSStorey RF. Curr Pharm Des. 2006;12:1255-59.

Tienopiridine: principali limitiTienopiridine: principali limitip p pp p p

• Ridotta potenza antiaggregante (problema per DES)

• Resistenza/risposta individuale variabile

• Profarmaci Latenza azione(problema per PCI urgenti)

• Inibitori irreversibili P2Y12 Durata azione• Inibitori irreversibili P2Y12 Durata azione(problema per CABG)

Angelo Sante Bongo

i nuovi antipiastrinici…i nuovi antipiastrinici…pp

•Prasugrel

•AZD6140•AZD6140

•Cangrelor

•TRA-SCH 530348

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Antiplatelet therapies in ACSAntiplatelet therapies in ACS

ADP-antagonistsOral

Cl id l i di t t d i t i lClopidogrel – indirect agent, dosing trialsPrasugrel – indirect agentAZ 6310 direct competitive agentAZ-6310 – direct competitive agent

IVCangrelor – direct competitive agentCangrelor direct competitive agent

Glycoprotein IIb/IIIa inhibitorsPAR (thrombin) receptor antagonist (TRA)( ) p g ( )

Angelo Sante Bongo

Antiplatelet therapies in ACSADP-antagonists

OralCl id l i di t t d i t i lClopidogrel – indirect agent, dosing trialsPrasugrel – indirect agentAZ 6310 direct competitive agentAZ-6310 – direct competitive agent



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Balance of efficacy and safety

15 138events

efficacy and safety

HR 0.81(0.73-0.90)P 0 0004

Clopidogrel

)

12.1CV death / MI / stroke

10P = 0.0004

Prasugrel

poin

t (% 9.9

NNT = 46

End

p

355

HR 1.32Prasugrel 2 4

35events

TIMI major NonCABG bleeds

0

(1.03-1.68)P = 0.03

Clopidogrel1.82.4NonCABG bleeds

NNH = 167

Angelo Sante Bongo

00 30 60 90 180 270 360 450

Days

Prasugrel:n n o a più potente tienopi idina

Prasugrel:n n o a più potente tienopi idinaun nuova, più potente tienopiridinaun nuova, più potente tienopiridina

prasugrelprasugrelp gp g

clopidogrelclopidogrel

Angelo Sante Bongo Jernberg et al, Eur Heart J 2006;27;1166-1173.Jernberg et al, Eur Heart J 2006;27;1166-1173.

Prasugrel: meno non-respondersPrasugrel: meno non-respondersg pg p

acutoacuto cronicocronicoacutoacuto cronicocronico

Angelo Sante BongoJernberg et al, Eur Heart J 2006;27;1166-1173.Jernberg et al, Eur Heart J 2006;27;1166-1173.

Antiplatelet therapies in ACSADP-antagonists

OralCl id l i di t t d i t i lClopidogrel – indirect agent, dosing trialsPrasugrel – indirect agentAZ 6310 direct competitive agentAZ-6310 – direct competitive agent



Angelo Sante Bongo

Angelo Sante Bongo

Antithrombotic treatment options

• Elective PCI To maximize the effectiveness ofElective PCI

• N-STEMI ACS

To maximize the effectiveness of

therapy and reduce the hazard of

bleeding ischaemic and bleeding risksN STEMI ACS

• STEMI

bleeding, ischaemic and bleeding risks

should be evaluated on an individual

b iSTEMI basis

Angelo Sante BongoEuropean Heart Journal ;doi:10.1093/eurheartj/ehq277


• Elective PCIElective PCI

• N-STEMI ACSN STEMI ACS

• STEMISTEMI


Antiplatelet therapy ELECTIVE PCI

ASA 150–300 mg per os or 250 (–500) mg bolus i v followed by 75–ASA 150–300 mg per os or 250 (–500) mg bolus i.v. followed by 75–100 mg per os daily

Clopidogrel 300 (600)-mg loading dose followed by75 mg daily for all patients75 mg daily for all patients300 mg at least 6 h before PCI600 mg at least 2 h before PCI


GPIs Should be used only in ‘bail-out’ situations(thrombus, slow flow, vessel closure, very complex lesions)

Anticoagulation therapy ELECTIVE PCI

UFH 70–100 IU/kg i v bolus without GPIsUFH 70–100 IU/kg i.v. bolus without GPIs50–70 IU/kg with GPIs

Enoxaparin





• STEMISTEMI


N-STEMI ACS

•High ischaemic risk is associated with ST-segment changes, elevated troponin, diabetes, and a GRACE score >140>140.

• A high bleeding risk is associated with female sex, ageA high bleeding risk is associated with female sex, age >75 years, bleeding history, GFR <30 mL/min, and use of femoral access.

Angelo Sante Bongo European Heart Journal ;doi:10.1093/eurheartj/ehq277

Antiplatelet therapy N-STEMI ACS

Angelo Sante Bongo

European Heart Journal ;doi:10.1093/eurheartj/ehq277

Antiplatelet therapy N-STEMI ACS

ASA 150–300 mg per os or 250 (–500) mg i.v. bolusfollowed by 75–100 mg daily

Clopidogrel • 600 mg loading dose followed by 75 mg dailyClopidogrel 600 mg loading dose, followed by 75 mg daily,• Prasugrel 60 mg loading dose, followed by 10 mg daily,• Ticagrelor 180 mg loading dose, followed by 90 mg twice daily

GPIs Should be used only in ‘bail out’ situationsGPIs Should be used only in bail-out situations(thrombus, slow flow, vessel closure, very complex lesions)Recent trials did not demonstrate additional benefit of GPIs after a clopidogrel loading dose of 600 mgclopidogrel loading dose of 600 mg

Severe bleeding complications increase with prasugrel use, specifically in patients with a history of stroke and TIA in the elderly (≥75 years) and in underweight


with a history of stroke and TIA, in the elderly (≥75 years), and in underweight patients (60 kg)

ISAR-REACT 2 N-STEMI ACS

Angelo Sante Bongo Kastrati et al, JAMA. 2006;295:(doi:10.1001/jama.295.13.joc60034)

Anticoagulation therapy – before cath lab N-STEMI ACS

GOLDEN RULES:

Avoid crossover especially between UFH and low molecular weight heparin (LMWH)molecular weight heparin (LMWH)

To discontinue antithrombins after PCI except in pspecific individual situations (e.g. thrombotic complication)

Angelo Sante Bongo European Heart Journal ;doi:10.1093/eurheartj/ehq277RISK STRATIFICATION

Anticoagulation therapyVery high risk of ischemia (persistent angina haemodynamic instability refractory arrhythmia)

N-STEMI ACS

Very high risk of ischemia (persistent angina, haemodynamic instability, refractory arrhythmia)

UFH 60 IU/kg i v bolus followed by infusion until PCIUFH 60 IU/kg i.v. bolus, followed by infusion until PCIBivalirudin (monotherapy)hi h bl di i k t

0.75 mg/kg bolus followed by 1.75 mg/kg/h

high bleeding risk pts


Anticoagulation therapyMedium to high risk of ischemia (troponin positive recurrent angina dynamic ST changes)

N-STEMI ACS

Medium to high risk of ischemia (troponin positive,recurrent angina, dynamic ST changes) (invasive strategy is planned within 24 (–48)

UFH UFH 60 IU/kg i.v. bolus, then infusion until PCI (ACT tritation)Enoxaparin 1 mg/kg subcutaneous (s.c.) twice daily until PCI (0,75 mg/kg

in pts > 75 y.o.)Fondaparinux 2.5 mg daily s.c. until PCI


Fondaparinux 2.5 mg daily s.c. until PCIBivalirudin 0.1 mg/kg bolus followed by 0.25 mg/kg/h

Anticoagulation therapyLow risk of ischemia (troponin negative no ST segment changes)

N-STEMI ACS

Low risk of ischemia (troponin negative, no ST-segment changes)

f d i 2 5 d ilfondaparinux 2.5 mg s.c. dailyenoxaparin 1 mg/kg s.c. twice daily (0.75 mg in patients ≥75

years)UFH 60 IU/kg i.v. bolus followed by infusion (aPTT

controlled).

Angelo Sante Bongo


Anticoagulation therapy – during cath lab N-STEMI ACS

UFH Continue infusion, ACT target range:200 250 s with GPIs•200–250 s with GPIs

• 250–350 s without GPIsEnoxaparin • less than 8 h since last s.c. appl.: no additional bolus;

• within 8–12 h of last s.c. appl.: add 0.30 mg/kg i.v. bolus;• >12 h since last s.c. appl.: 0.75 mg/kg i.v. bolus.

Fondaparinux Add UFH 50–100 IU/kg when PCI is performed.Bivalirudin Add an additional i.v. bolus of 0.5 mg/kg and increase the

infusion rate to 1.75 mg/kg/h before PCI.

Angelo Sante Bongo





• STEMISTEMI



• High ischaemic risk is associated with ST-segment changes, elevated troponin, diabetes, and GRACE score > 140

• High bleeding risk is associated with female sex, age > 75 years, bleeding history, GFR < 30 mL/min, and use of femoral access

Angelo Sante Bongo


Antiplatelet therapy STEMI ACS


Antiplatelet therapy STEMI ACS

ASA 150–300 mg per os or 250 (–500) mg i.v. bolusfollowed by 75–100 mg daily

DAPT • Prasugrel 60 mg loading dose, followed by 10 mg daily,• Ticagrelor 180 mg loading dose, followed by 90 mg twice daily• Clopidogrel 600 mg loading dose, followed by 75 mg daily (if other not available)

GPIs The controversial literature data, the negative outcome of the only prospective RCT and the beneficial effects of faster acting and moreprospective RCT, and the beneficial effects of faster acting and more efficacious ADP receptor blockers in primary PCI do not support pre-hospital or pre-catheterization use of GPIIb–IIIa inhibitors.


TRITON – TIMI - 38 STEMI ACS

Angelo Sante Bongo N Engl J Med 2007;357:2001-15

De Luca, G. et al. JAMA 2005;293:1759-1765.

METANALISI - Abciximab STEMI ACS

, ;

• Primary• Mortality at 30 days• Mortality at 6 and 12 months

• Secondary• Reinfarction at 30 days

Angelo Sante Bongo

HORIZONS - AMI STEMI ACS

Angelo Sante Bongo

N Engl J Med 2008;358:2218-30

Anticoagulation therapy STEMI ACS

UFH 60 IU/k i ith GPIUFH 60 IU/kg i.v. with GPIs100 IU/kg i.v. without GPIs

Bivalirudin 0.75 mg/kg bolus followed by 1.75 mg/kg/h

A recent study suggested bivalirudin monotherapy as an alternative to UFH plus a GPIIb–IIIa inhibitor.255 Significantly lower severe bleeding rates led to a beneficial net clinical outcome indicating that bivalirudin may be preferred in STEMI patients at high


clinical outcome indicating that bivalirudin may be preferred in STEMI patients at high risk of bleeding. One-year outcome of the HORIZONS RCT confirmed the beneficial action of bivalirudin monotherapy vs. UFH and a GPIIb–IIIa inhibitor.

Impatto delle nuove linee guida nell’attività interventistica:

Rivascolarizzazione miocardica nelleConclusioni miocardica nelle

SCAConclusioni1. La doppia antiaggregazione è un trattamento assodato e

irrinunciabile2. Le nuove tienopiridine offrono vantaggi sul fronte

antitrombotico ma possono incrementare il rischio emorragico

3. Dobbiamo abituarci ,prima dell'avvio del trattamento antitrombotico, a stratificare il rischio emorragico del paziente

4. Gli inibitori glicoproteine devono essere usati nei paziento lt i hi t b ti t b i id t i “b il t “con alto rischio trombotico e trombosi evidente , in “bail out “

ma non in “upstream”.5. Non embricare tipi diversi di eparina 6 Considerare l'uso di bivalirudina come alternativa all'eparina6. Considerare l'uso di bivalirudina come alternativa all'eparina

nei pazienti ad altro rischio emorragico

Angelo Sante Bongo

C l i

Impatto delle nuove linee guida nell’attività interventistica:

Rivascolarizzazione miocardica nelleConclusione miocardica nelle

SCA

Angelo Sante Bongo

Rivascolarizzazione miocardica nelle SCAdeart.s3.amazonaws.com/dreamsas/2011/Prando.pdf ·...

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