ALMA MATER STUDIORUM

UNIVERSITA’ DI BOLOGNA

Geometrie variabili nella scelta della

terapia antiaggregante nelle SCA

Francesco SaiaIstituto di Cardiologia – Università di Bologna

Policlinico S. Orsola – MalpighiBologna

Lucca, 28 Novembre 2013

1. Adhesion

2. Activation

3. Aggregation

Resting platelet

The Role of Platelets in AtherothrombosisThe Role of Platelets in Atherothrombosis

The Role of Platelets in AtherothrombosisThe Role of Platelets in Atherothrombosis

Coagulation cascade

Molecular targets of antiplatelet agentsMolecular targets of antiplatelet agents

Michelson AD. Nature Reviews Drug Discovery 2010; 9:154-169

(Incomplete) List of hot topics on antiplatelet Rx(Incomplete) List of hot topics on antiplatelet Rx

� Type of agent, characteristics, evidence for use (old and new drugs)

� Dosage (e.g. bolus dose for oral agents, GPI bolus vs. bolus+infusion)

� Way of administration (e.g. GPI i.c. vs i.v.)

� Combination of drugs (e.g. antiplatelet+anticoagulant)

� Timing of administration with respect to diagnosis (e.g. pre-treatment vs. no

pre-tx in ACS)

� Drug-drug interaction (e.g. clopidogrel and PPI)

� Length of prescription

� Tailored treatment:

� Baseline clinical parameters (e.g. high risk ACS, DM,coronary anatomy..)

� Treatment strategy (e.g. conservative vs. invasive)

� Laboratory parameters (e.g. bedside monitoring of on-treatment

antiplatelet reactivity and dose-adjustement)

ISIS-2: Lancet 1988;2:349-60

Antiplatelet Trialists' Collaboration BMJ 1994;308: 81-106

High- vs. low-dose ASA in ACS: CURRENT OASIS 7High- vs. low-dose ASA in ACS: CURRENT OASIS 7

CURRENT-OASIS 7 Investigators. N EJM 2010; 363:930-42

ASA

75-100 mg

ASA

300-325 mg

HR 95% CI P

CV Death/MI/Stroke

PCI (2N=17,232) 4.2 4.1 0.98 0.84-1.13 0.76

No PCI (2N=7855) 4.7 4.4 0.92 0.75-1.14 0.44

Overall (2N=25,087) 4.4 4.2 0.96 0.85-1.08 0.47

Stent Thrombosis 2.1 1.9 0.91 0.73-1.12 0.37

TIMI Major Bleed 1.03 0.97 0.94 0.73-1.21 0.71

CURRENT Major Bleed

2.3 2.3 0.99 0.84-1.17 0.90

CURRENT Severe Bleed

1.7 1.7 1.00 0.83-1.21 1.00

GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051

Primary Outcome and BleedingPrimary Outcome and Bleeding

CURRENT-OASIS 7 Investigators. N EJM 2010; 363:930-42

Mahaffey KW, et al. Circulation 2010; 124: 544-54

Aspirin dose and ticagrelor: insights from PLATOAspirin dose and ticagrelor: insights from PLATO

• Median aspirin dose ≥300 mg/d 53.6% US vs. 1.7% in the rest of the world

• No similar observation with prasugrel � Drug-specific? Play of chance?

A future without ASA? A future without ASA?

New P2Y12 inhibitors vs. clopidogrelNew P2Y12 inhibitors vs. clopidogrel

Wiviott SD, et al. N Engl J Med 2007;357: 2001-15Wallentin L, et al. N Engl J Med 2009; 361: 1045-57

Hamm CW et al. Eur Heart J. 2011;32:2999-3054

STEMI Guidelines 2012

NSTE-ACS Guidelines 2011

ESC GuidelinesESC Guidelines

Steg G, et al. Eur Heart J .2012;33, 2569–2619

Which drug after ASA?Which drug after ASA?

Clopidogrel Ticagrelor Prasugrel

Prasugrel in STEMI: TRITON-TIMI 38Prasugrel in STEMI: TRITON-TIMI 38

Montalescot G, et al. Lancet. 2009;373: 723-31

• Rapid efficacy

• 31% of the patients pre-treated

• No significative interaction between primary and secondary PCI

Ticagrelor in STEMI: PLATOTicagrelor in STEMI: PLATO

Steg PG, et al. Circulation 2010;122:2131-41

• Delayed efficacy

• Worrisome findings on stroke

• Possible problems with AV blocks and interpretation of dyspnea

Reduction of stent thrombosisReduction of stent thrombosis

Ferreiro JL and Angiolillo DJ. Circ Cardiovasc Intvn 2012; 2012;5:433-445

The tradeoff between efficacy and bleeding is most favorable around day 12, exhibits a

gentle “plateau” through approximately day 30, and declines through day 80, as the

numbers of attributable bleeding events outpace the number of endpoint events

prevented

Average daily event rates after PPCI: HORIZONS AMIAverage daily event rates after PPCI: HORIZONS AMI

G. Stone. TCT 2013

Time of enrollment in PLATO and TRITONTime of enrollment in PLATO and TRITON

ACS Patient

UA/NSTEMI

Admission Initial Management

Angiography

Conservative strategy

Conservative strategy or

CABG

Enrollment Enrollment

PCI

7.9

4.1

Clopidogrel

Ticagrelor

HR=0.52; 95% CI 0.32-0.85; p<0.001

Held C, et al. J Am Coll Cardiol 2011; 57:672–84

Ticagrelor in patients undergoing CABGTicagrelor in patients undergoing CABG

CV death

Ticagrelor in patients undergoing CABGTicagrelor in patients undergoing CABG

Held C, et al. J Am Coll Cardiol 2011; 57:672–84

59,3

21,0

10,6

43,7

0,8

57,6

21,6

12,2

42,6

1,00,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

TIMI major

bleed

TIMI minor Gusto severe Life-threat Fatal bleed

Ticagrelor

Clopidogrel

Ticagrelor in pts intended for non-invasive managem entTicagrelor in pts intended for non-invasive managem ent

James S, et al. BMJ. 2011 Jun 17;342:d3527

Prasugrel in pre-treatment in ACS: ACCOASTPrasugrel in pre-treatment in ACS: ACCOAST

Montalescot G, et al. N Engl J Med 2013;369:999-1010.

Primary EP: CVD, MI, stroke, urg revasc, or GPI bailout

Prasugrel in ACS pts without revascularizationPrasugrel in ACS pts without revascularization

Roe MT et al. N Engl J Med. 2012; 367:1297-309

Overall population

Is there still a role for GPIs ? Is there still a role for GPIs ?

Bivalirudin vs. Hep+GPI: EUROMAXBivalirudin vs. Hep+GPI: EUROMAX

Steg PG. N Engl J Med. 2013 Oct 30. [Epub ahead of print]

The primary endpoint is driven by bleeding as defin ed in the study

Bivalirudin (N=1089) Heparins with optional GPI (N=1109)

P value

Death 32 (2.9%) 34 (3.1%) 0.86

Bleedings 28 (2.6%) 67 (6.0%) <0.001

Stent thrombosis in bivalirudin trials in STEMI Stent thrombosis in bivalirudin trials in STEMI

Steg PG. N Engl J Med. 2013 Oct 30. [Epub ahead of print]

p=0.09

p<0.001 p=0.02 P=0.007

Stone G. N Engl J Med. 2008; 358:2218-30

Parodi G et al. J Am Coll Cardiol 2013; 61:1601–6

Prasugrel vs Ticagrelor in STEMI: RAPID-PCIPrasugrel vs Ticagrelor in STEMI: RAPID-PCI

After 2h around 50% of the patients have insufficient

platelet inhibition

Valgimigli M et al, J Am Coll Cardiol Intv 2012;5:268–77

GPI bolus + prasugrel: FABOLUS PROGPI bolus + prasugrel: FABOLUS PRO

P for interaction = 0.0254

p = 0.03 p = 0.34

Visible thrombus: “Block and Bridge”Visible thrombus: “Block and Bridge”

Christ G, et al. Thrombosis Research 2013; in press

Abciximab bolus only

on top of

Clopidogrel 600 mg or Prasugrel 60 mg

UFH/En+GPI vs bivalirudin: ACUITYUFH/En+GPI vs bivalirudin: ACUITY

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)

Primary endpoint (ITT)

PNI <0.0001PSup = 0.015

PNI = 0.011PSup = 0.32

PNI <0.0001PSup <0.0001

Stone G, et al. N Engl J Med 2006; 355 :2203-16

Prognostic value of HTPR in the ISAR-REACT 4Prognostic value of HTPR in the ISAR-REACT 4

Sibbing, et al. J Am Coll Cardiol. 2012;60:369-77

OR 5.4; 95% CI 2.4-12.1P<0.0001

OR 1.4P=NS

Immediate vs delayed PCI: ABOARDImmediate vs delayed PCI: ABOARD

0 20 40 60 80 100

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Troponin I (ng/mL)

Den

sity

in the immediate and delayed groups

immediate groupdelayed group

Primary EP: peak values of troponin I

Median, IQR

2.1 (0.3-7.1)1.7 (0.3-7.2)

p = 0.70

Montalescot G, et al. JAMA 2009; 302;9:947-954

All PCIs on abciximab

• A strategy of

immediate PCI is not

superior to a strategy

of early delayed PCI

• When immediate PCI

is required, full

antiplatelet treatment

may avoid the “early

hazard” related to the

procedure

CI-37

Cangrelor– Parenteral administration

– Direct platelet P2Y12 receptor antagonist

– ATP analogue (MW=800 Daltons)

– T1/2 ≈ 3 to 6 minutes

– Offset ≈ 60 minutes

– Metabolism not dependent on renal or hepatic function

N N

N N

NH

SCF3

OHOH

OO

PO

O

PP

OO

OClCl

OO

O

S

4Na+

Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012;34:44-55.

CI-38

Recovery time~60 minutes

dose 30ug/kg bolus + 4ug/kg/min infusion

Con

cent

ratio

n (n

g/m

L)

% P

late

let A

ggre

gatio

n (im

peda

nce)

Time (minutes)0

20

40

60

80

100

120

140

160

0

100

200

300

400

500

600

700

800

0 20 40 60 80 100 120 140 160

Platelet activity

Plasmaconcentration

infusion

bolus

Akers J Clin Pharmacol. 2010;50:27-35

Genereux P, et al. JACC 2013; in press

Insights from the CHAMPION PHOENIX

Impact of intra-procedural Stent ThrombosisImpact of intra-procedural Stent Thrombosis

Impact of intra-procedural Stent ThrombosisImpact of intra-procedural Stent Thrombosis

Genereux P, et al. JACC 2013; in press

Insights from the CHAMPION PHOENIX

Bivalirudin - Cangrelor synergy to avoid early thrombotic hazard

Mortality for STEMI without

cardiogenic shock

Adapted from Capranzano et al. Expert Rev. Cardiovasc. Ther. 2012; 10:411.422

Cangrelor Infusion Stop

Cangrelor Infusion Start Prasugrel or Ticagrelor LD

ConclusioniConclusioni� ASA low-dose (75-100 mg) after the acute phase in a ll patients

� GPIs (bolus-only) in selected STEMI patients (high- risk, early presenters)

and in high-risk NSTEMI patients not adequately pre -treated, associated

with strategies for bleeding risk reduction

� P2Y12 antagonists

� STEMI ���� Prasugrel (except previous CVA; caveat for weight<60 Kg and

age >75)

� NSTEMI ���� Ticagrelor

� Clopidogrel in patients at high-risk of bleeding (e .g. OAT, age and

multiple comorbidity, previous severe bleeding or a ctive bleeding etc..)

� When bivalirudin is used, more potent P2Y12 antagon ists should be

preferred over clopidogrel. Bridge with Cangrelor h olds a strong rationale

(but costs may be relevant)