Impatto delle nuove linee guida ll’ tti ità i t ti tinell’attività interventistica:
RivascolarizzazioneRivascolarizzazione miocardica nelle
SCASCA
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Trattamento antitrombotico inTrattamento antitrombotico in corso di IMAcorso di IMA
RischioRischio
trombotico
Rischio emorragico
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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
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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
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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
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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
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* 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
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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
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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)
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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 ( )
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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
IVCangrelor – direct competitive agentCangrelor direct competitive agent
Glycoprotein IIb/IIIa inhibitorsPAR (thrombin) receptor antagonist (TRA)( ) p g ( )
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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
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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
IVCangrelor – direct competitive agentCangrelor direct competitive agent
Glycoprotein IIb/IIIa inhibitorsPAR (thrombin) receptor antagonist (TRA)( ) p g ( )
Angelo Sante Bongo
Angelo Sante Bongo
Angelo Sante Bongo
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
Antithrombotic treatment options
• Elective PCIElective PCI
• N-STEMI ACSN STEMI ACS
• STEMISTEMI
Angelo Sante BongoEuropean Heart Journal ;doi:10.1093/eurheartj/ehq277
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
Angelo Sante BongoEuropean Heart Journal ;doi:10.1093/eurheartj/ehq277
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
Angelo Sante BongoEuropean Heart Journal ;doi:10.1093/eurheartj/ehq277
Antithrombotic treatment options
• Elective PCIElective PCI
• N-STEMI ACSN STEMI ACS
• STEMISTEMI
Angelo Sante BongoEuropean Heart Journal ;doi:10.1093/eurheartj/ehq277
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
Angelo Sante BongoEuropean Heart Journal ;doi:10.1093/eurheartj/ehq277
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
Angelo Sante BongoEuropean Heart Journal ;doi:10.1093/eurheartj/ehq277
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
Angelo Sante Bongo European Heart Journal ;doi:10.1093/eurheartj/ehq277
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
European Heart Journal ;doi:10.1093/eurheartj/ehq277
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
European Heart Journal ;doi:10.1093/eurheartj/ehq277
Antithrombotic treatment options
• Elective PCIElective PCI
• N-STEMI ACSN STEMI ACS
• STEMISTEMI
Angelo Sante Bongo European Heart Journal ;doi:10.1093/eurheartj/ehq277
Antithrombotic treatment options
• 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
European Heart Journal ;doi:10.1093/eurheartj/ehq277
Antiplatelet therapy STEMI ACS
Angelo Sante BongoEuropean Heart Journal ;doi:10.1093/eurheartj/ehq277
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.
Angelo Sante Bongo European Heart Journal ;doi:10.1093/eurheartj/ehq277
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
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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
Angelo Sante Bongo European Heart Journal ;doi:10.1093/eurheartj/ehq277
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