Nuove evidenze sullimpiego di antiaggreganti e anticoagulanti nello STEMI e nelle SCA NSTE Francesco...

Nuove evidenze sull’impiego di antiaggreganti e anticoagulanti nello

STEMI e nelle SCA NSTE

Francesco Bovenzi

Dipartimento Cardio-RespiratorioU.O. di Cardiologia, Ospedale “Campo di Marte” Lucca LUCCA

CARDIOLOGIA

SYNERGY

LMWH

ESSENCE

1997

CURE

Clopidogrel

Ischemic risk

GP IIb/IIIa blockers

PRISM-PLUS

PURSUIT

ACUITYTACTICS TIMI-18

Early invasive

PCI ~ 5% stents ~85% stents Drug-eluting stents

ISAR-REACT 2

Milestones in ACS Management

OASIS-5

FondaparinuxAnti-Thrombin Rx

Anti-Platelet Rx

Treatment Strategy

Heparin

Aspirin

Conservative

ICTUS

Bivalirudin

REPLACE 2

Bleeding risk

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20022002 20032003 20042004 20052005 2006 20102006 20102001200119901990

TRITON Timi 38

Prasugrel

CURRENT OASIS-7

PLATO

Ticagrenor

The result is 80 different combinations!

Extreme attention should be paid to the use of drugs or drug combinations and

dosages that may favour bleeding

Atalanta ACC 2010Eugene Braunwald

“I più potenti inibitori delle piastrine sono stati studiati nel TRITON TIMI-38 e nel PLATO che hanno posto le basi per l’alba di una nuova era della terapia antipiastrinica.

Finora non c’è stato nulla di “free lunch”, perché quando interveniamo sulla coagulazione troveremo associato, in ogni modo, un eccesso di sanguinamento.

La nostra futura sfida sarà trovare uno “sweet spot” nella ricerca di bilanciare l’efficacia con la sicurezza.”

Primary Therapeutic Goal for ACS

•Prevent the development of occlusive thrombus

•Arrest procoagulant activity and inflammation

•Attenuate platelet activation and aggregation

•Promote platelet disaggregation

•Facilitate perfusion

The Key Platelet Transmembrane Receptors

AA

ADP PGI2

IP

TXA2

TP

PLCCa++

ADP

Gq

+

IP3

Ca++

Ca++

AC

GS

+Gi

-

ATP

cAMP+ -

P2X1 P2Y1

ADP

P2Y12

Activation of GPIIb/IIIa

Binding of soluble fibrinogen

Aggregation

PGH2

TAX2

COX

TAXS

PAR

TRAP

AA

ADP PGI2

IP

TXA2

TP

PLCCa++

ADP

Gq

+

IP3

Ca++

Ca++

AC

GS

+Gi

-

ATP

cAMP+ -

P2X1 P2Y1

ADP

P2Y12



Aggregation

PGH2

TAX2

COX

TAXS

PAR

TRAP

Conventional Antiplatelet Agents

ASA

ClopidrogelTiclopidina

ReoproTirofibanEptifibatide

AA

ADP PGI2

IP

TXA2

TP

PLCCa++

ADP

Gq

+

IP3

Ca++

Ca++

AC

GS

+Gi

-

ATP

cAMP+ -

P2X1 P2Y1

ADP

P2Y12



Aggregation

PGH2

TAX2

COX

TAXS

PAR

TRAP


ASA



PrasugrelTicagrelorCangrelor

AA

ADP PGI2

IP

TXA2

TP

PLCCa++

ADP

Gq

+

IP3

Ca++

Ca++

AC

GS

+Gi

-

ATP

cAMP+ -

P2X1 P2Y1

ADP

P2Y12



Aggregation

PGH2

TAX2

COX

TAXS

PAR

TRAP


ASA



PrasugrelTicagrelorCangrelor

SCH530348

P2Y12 inhibitors

AC+

Gi

-

ATP

cAMP

P2Y12

Ticlopidine and clopidogrel

• Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite

• Irreversibly inhibiting the receptor

• Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.

P2Y12 inhibitors

AC+

Gi

-

ATP

cAMP

P2Y12





Prasugrel

• Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel


• More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel

P2Y12 inhibitors

AC+

Gi

-

ATPcAMP

P2Y12





Prasugrel




Ticagrelor

• Not a prodrug

• Rapid onset of inhibitory effect

•Reversibly bound with faster offset of effect and functional recovery of all circulating platelets

P2Y12 inhibitors

AC+

Gi

-

ATPcAMP

P2Y12Ticlopidine and clopidogrel




Prasugrel




Ticagrelor

• Not a prodrug

• Rapid onset of inhibitory effect

•Reversibly bound with faster offset of effect and functional recovery of all circulating platelets

Cangrelor

• ATP analogue

• Reversible binds to and inhibits the P2Y12 ADP receptor

• Immediately active after i.v. infusion

New P2Y12 inhibitors

AC+

Gi-

ATPcAMP

P2Y12

Elinogrel

Direct-acting, reversible P2Y12 inhibitor that can be administeredboth intravenously and orally

A Phase 2 Safety and Efficacy Study of Elinogrel a Novel Intravenous and Oral P2Y12 Inhibitor in Non-Urgent PCI (INNOVATE-PCI) is a multicenter, randomized, double-blind, triple-dummy,clopidogrel-controlled study of intravenous and oral elinogrelcompared with clopidogrel in patients undergoing nonurgent (including elective) PCI. After diagnostic angiography, patientsscheduled for nonurgent PCI will be randomized to clopidogrel or 1 of 3 doses of elinogrel.

The Early Rapid Reversal of Platelet Thrombosis With Intravenous Elinogrel Before PCI to Optimize Reperfusionin Acute MI (ERASE-MI) is a randomizedtrial evaluating the safety and tolerability of intravenous elinogrel (10, 20, 40,and 60 mg) before PCI in patients with STEMI

I ragionevoli dubbi con terapia anticoagulante e antiaggregante• Quale è il rischio e l’impatto degli eventi aterotrombotici

nelle SCA?• Quale è il rischio e l’outcome dei sanguinamenti nelle

SCA?• Esiste un compromesso clinico tra rischio emorragico e

beneficio della doppia antiaggregazione?• Quanto incide la biodiversità sulle scelte?• Quale è il timing del rischio di sanguinamento• Come affrontare il rischio di sanguinamento correlato ad

altre procedure invasive

Partiamo dalle evidenze dei tre ultimi grandi trial

Factorial Randomized Trial (2X2) of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI

Factorial Randomized Trial (2X2) of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI

Non ancora pubblica

to!

OASIS-7

2007

2009

ESC 2009

Study Design, Flow and Compliance25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)

Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

PCI 17,232(70%)

Angio 24,769(99%)

Angio 24,769(99%)

No PCI 7,855 (30%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

Randomized to receive (2 X 2 factorial):

CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)

ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Complete Follow up

99.8%

Complete Follow up

99.8%

Clopidogrel: Double vs Standard DosePrimary Outcome and Components

Standard Double HR 95% CI P Intn P

CV Death/MI/Stroke

PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.0360.016

No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14

Overall (2N=25,087) 4.4 4.2 0.94 0.84-1.07 0.370

MI

PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.0120.025

No PCI (2N=7855) 1.4 1.7 1.25 0.87-1.79 0.23

Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097

CV Death

PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.681.0

No PCI (2N=7855) 2.8 2.7 0.96 0.74-1.26 0.77

Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628

Stroke

PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.590.50

No PCI (2N=7855) 0.8 0.9 1.11 0.68-1.82 0.67

Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.8595% CI 0.74-0.99

P=0.036

15% RRR15% RRR

CV Death, MI or StrokeCV Death, MI or Stroke

Days

Cu

mu

lati

ve H

azar

d

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard Dose

Clopidogrel Double Dose

42% RRR

HR 0.5895% CI 0.42-0.79

P=0.001

Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)

ConclusionsClopidogrel Dose Comparison

1. Double-dose clopidogrel significantly reduced major CV events in PCI (CV death, MI or stroke) and stent thrombosis

2. In patients not undergoing PCI double dose clopidogrel was not significantly different from standard dose

3. There was a modest excess in CURRENT-defined major bleeds but no difference in severe: TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds

Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolisis in MI

TRITON-TIMI 38: Balance of efficacy and safety

15

10

5

00 30 60 90 180 270 360 450

1.8

2.4

9.9

12.1

138 events

HR 0.81(0.73-0.90)p=0.0004NNT=46

35 events

HR 1.32(1.03-1.68)p=0.03NNH=167

Wiovitt SD et al. NEJM 2007

(6795 pts)

(6813 pts)

Diabetic SubgroupDiabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

dp

oin

t (%

)

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 20 (46)

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

Montalescot G et al. Lancet 2008;372:1-9; Wiviott SD, N Engl J Med 2007;357(20):2001-15

TRITON-TIMI 38: Timing of benefit

0

2

4

6

8

0 1 2 3 3060 90 180 270 360 450 Days0

Loading Dose Maintenance Dose

Prim

ary

End

poin

t (%

)


(6795 pts)

(6813 pts)

TRITON-TIMI 38: Stent Thrombosis (ARC Definite + Probable)

0 30 60 90 180 270 360 4500

1

2

3

Days

En

dpo

int (

%)


TRITON-TIMI 38: Bleeding

0

2

4

Eve

nts

(%)

TIMI MajorBleedsARD 0.6%HR 1.32p=0.03NNH=167

LifeThreateningARD 0.5%HR 1.52p=0.01

Non fatal

ARD 0.2%p=0.23

Fatal

ARD 0.3%p=0.002

ICH

ARD 0%p=0.74


OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)

+ 37

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36


TRITON-TIMI 38: Bleeding risk subgroups

Safety

Significant increase in

serious bleeding(32% increase)

Avoid in pts with prior CVA/TIA

Efficacy

1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%

MI 24%

2. An early and sustained benefit

3. Across ACS spectrum

Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD

Higher IPA to Support PCI

Net clinical benefit significantly favored Prasugrel

Optimization of Prasugrel maintenance dosing in a minority of patients

may help improve the benefit: risk balance

Bleeding Risk SubgroupsTherapeutic Considerations

Significant Net Clinical Benefit

with Prasugrel80%

MD MD 10 mg10 mg

Reduced MD

Guided by PK

Age > 75 or

Wt < 60 kg

16%

Avo

id

Prasu

grel

Prio

r

CV

A/T

IA4%4%

Antman EM, AHA 2007

Study of Platelet Inhibition and Patient Outcomes: PLATO Study Design

Days after randomisation

Cum

ulat

ive

inci

denc

e (%

)

PLATO: Primary efficacy endpoint(CV death,MI or stroke)

Wallentin L et al. NEJM 2009

0 60 120 180 240 300 360

0

2

4

6

8

10

12 11.7

9.8

(9.291 pts)

(9.333 pts)

0 60 120 180 240 300 360 0 60 120 180 240 300 360

0

1

2

3

4

5

6

7

0

1

2

3

4

5

6

7

Days after randomization Days after randomization

Cum

ulat

ive

inci

denc

e (%

)

Cum

ulat

ive

inci

denc

e (%

)

Myocardial Infarction Cardiovascular death

PLATO: Secondary efficacy endpoints


0 60 120 180 240 300 360

0

5

10

15

K-M

est

imat

ed r

ate

(% p

er y

ears

)

Days from first IP doseWallentin L et al. NEJM 2009

PLATO: Primary safety event (total major bleeding)

(9.235 pts)

(9.186 pts)

0

1

2

3

4

5

6

7

8

9

Non-CABGTIMI major bleeding

Non-CABGPLATO major bleeding*

CABGPLATO major bleeding*

CABGTIMI major bleeding

K-M

est

imat

ed r

ate

(% p

er y

ears

)PLATO: Non CABG and CABG major bleeding


*Bleeding with clinically significant disability or associated with hemoglobin declive at least 3.0 g/dl but less 5.0 g/dl trasfusion of 2 to 3 units

No. at risk

Clopidogrel

Ticagrelor

6,676

6,732

6,157

6,268

6,062

6,173

5,917

Days after randomization

4,849

4,924

3,706

3,766

2,987

3,078

0 60 120 180 240 300 360

8

6

4

2

0

Cu

mu

lati

ve i

nci

de

nce

(%

)

Clopidogrel

Ticagrelor

5.3

6.6

6,010

0 60 120 180 240 300 360

8

4

2

0

Clopidogrel

Ticagrelor3.4

4.3

6

6,676

6,732

6,376

6,439

6,332

6,375

6,209

Days after randomization

5,114

5,141

3,917

3,591

3,164

3,2336,241

Myocardial infarction Cardiovascular death

Cu

mu

lati

ve i

nci

de

nce

(%

)

HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025

PLATO-invasive

Cannon PC et al. Lancet 2010

TicagrelorClopidogrel

NS

NS

NS

0

K-M

est

imat

ed r

ate

(% p

er y

ear)

PLATO major bleeding*

1

2

3

4

5

6

7

8

9

10

12

11

13

TIMI major bleeding

11.5 11.6

8.0 8.0

2.93.2

GUSTO severe bleeding*

4.7

4.1

2.8 2.3

1.9

1.7

No

n-C

AB

GC

AB

G

PLATO-invasive: Non-CABG and CABG-related major bleeding

Cannon PC et al. Lancet 2010

*Bleeding with clinically significant disability or associated with hemoglobin declive at least 3.0 g/dl but less 5.0 g/dl trasfusion of 2 to 3 units

- Inibisce in modo diretto la trombina legata al coagulo e circolante con uno specfico legame bivalente ai due siti - Non richiede la presenza dell'antitrombina- Inibisce la trombina mediata dall'attivazione piastrinica- Ha un'emivita plasmatica di 25 minuti- Non richiede monitoraggio

Luci e ombre della bivaliridina

Fibrina

Sito catalitico

Trombina

TrombinaTrombina

Trombina

Bivalirudina

1 2

Sito esterno

Study Design – Patient Flow

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategyModerate-high risk unstable angina or NSTEMI undergoing an invasive strategy

UFH/Enox+ GP IIb/IIIa(N=4,603)

Bivalirudin+ GP IIb/IIIa(N=4,604)

BivalirudinAlone(N=4,612)

R*

GPI upstream (N=2294)

GPI CCL for PCI (N=2309)

GPI upstream (N=2311)

GPI CCL for PCI (N=2293)

Aspirin in allAspirin in allClopidogrelClopidogreldosing and timingdosing and timingper local practiceper local practice

Aspirin in allAspirin in allClopidogrelClopidogreldosing and timingdosing and timingper local practiceper local practice

Moderate-high riskACS

ACUITY

Primary Endpoint Measures (ITT)

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

11,7%

7,3%5,7%

3,0%

10,1%

7,8%

Net clinicaloutcome

Ischemiccomposite

Major bleeding

30 d

ay e

vent

s (%

)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)

PNI <0.0001PSup = 0.015

PNI = 0.011PSup = 0.32

PNI <0.0001PSup <0.0001

ACUITY

Stone GW et al. N Engl J Med. 2006;355:2203–2216.

3602 randomized pts undergoing primary PCI3602 randomized pts undergoing primary PCI

Hypothesis: Use of the polymer-based slow-Use of the polymer-based slow-release release paclitaxel-eluting paclitaxel-eluting TAXUS stent will TAXUS stent will safely reduce the 1-year rate of ischemia-safely reduce the 1-year rate of ischemia-driven TLRdriven TLR

Hypothesis: Bivalirudin compared to UFH Bivalirudin compared to UFH + routine IIb/IIIa will r+ routine IIb/IIIa will reduce the composite educe the composite rate of death, reinfarction, TVR, stroke and rate of death, reinfarction, TVR, stroke and major bleeding at 30-daysmajor bleeding at 30-days

HORIZONS AMI Trial

UFH + UFH + IIb/IIIaIIb/IIIa

inhibitorinhibitor

BivalirudinBivalirudin++

bail-outbail-outIIb/IIIa IIb/IIIa

Randomize 1:1Randomize 1:1

Target vessel Target vessel stentingstenting

TAXUSTAXUSstentstent

Bare metal Bare metal Express stentExpress stent

Randomize 3:1Randomize 3:1

Anti-thrombotictherapy

HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in AMItents in AMI

UFH +GP IIb/IIIaN=1802

BivalirudinMonotherapyN=1800

R 1:1

RandomizedRandomized

30 day FU*30 day FU*

* Range ±7 days* Range ±7 days

ITT populationITT population

N=1778(98.7%)

N=1777(98.7%)

N=1802 N=1800

• • • • • • Withdrew • • •Withdrew • • •

• • • • • • Lost to FU • • •Lost to FU • • •99

15151010

1313

3602 pts with STEMI3602 pts with STEMI

Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30]

PPsupsup = 1.00 = 1.00

Primary Outcome Measures

Diff = Diff = -3.3% [-5.0, -1.6] RR RR = = 0.60 [0.46, 0.77]

PPNINI ≤ 0.0001 ≤ 0.0001

PPsupsup ≤ 0.0001 ≤ 0.0001

Diff = Diff = -2.9% [-4.9, -0.8]RR = RR = 0.76 [0.63, 0.92]

PPNINI ≤ 0.0001 ≤ 0.0001

PPsupsup = 0.006 = 0.006

1 endpoint 1 endpoint

Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

Conclusioni- I nuovi farmaci che bloccano il recettore P2Y12 (prasugrel, ticagrelor) sono risultati più efficaci del clopidogrel grazie ad una migliore farmacocinetica e farmacodinamica. Ad essi si associa tuttavia un certo grado di rischio emorragico.

- La bivalirudina riduce i sanguinamenti locali e d’organo nei pazienti con SCA sottoposti a PCI, soprattutto in quelli a maggior rischio emorragico (anziani), ma per un’efficace copertura anti-ischemica deve essere associata ad un regime di doppia anti-aggregazione piastrinica.

- L’analisi di efficacia e di rischio in particolari sottogruppi di pazienti con SCA potrà permettere di utilizzare il farmaco più vantaggioso per quel dato contesto clinico.

Nuove evidenze sullimpiego di antiaggreganti e anticoagulanti nello STEMI e nelle SCA NSTE Francesco...

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