Adjunctive antiplatelet

therapy in the settings of

primary PCI
Adam Witkowski, MD, PhD, FESC
Institute of Cardiology, Warsaw

ICI Tel Aviv, 07.12.2009

STEMI Guidelines

2008 ESC GUIDELINES: Management
of STEMI

ACC/AHA 2009 STEMI/PCI Guidelines

Focused Update
Reperfusion Therapy: Primary PCI
Recommendations Class LOE

Preferred reperfusion treatment if performed by an I A

experienced team as soon as possible after FMC

 Time from FMC to balloon should be < 2 h in any case I B

and < 90 min in pts presenting early (< 2 h) with large
infarct and low bleeding risk

 Indicated for patients in shock and those with I B

contraindications to fibrinolytic therapy irrespective of
time delay

Rescue PCI
 After failed fibrinolysis in patients with large infarcts if IIa A
performed within 12 h
 Fundamental Role of Platelets in ACS
Importance of Antiplatelet Therapy
1 Adhesion

Platelets
2
Plaque Activation
rupture
Activated
platelets
3 Aggregation
STEMI-occlusive thrombus TxA2
NSTEMI = partial lumen occlusion ADP Fibrinogen

1. Cannon CP et al. Heart Disease: A Textbook of Cardiovascular Medicine.

6th ed. Philadelphia, PA: WB Saunders, 2001: 1232–1263.
2. Antman EM. In: Califf RM, ed. Atlas of Heart Diseases,
VIII. Philadelphia, PA: Current Medicine, 1996.
Antiplatelets co-therapy in pPCI
ESC 2008 Guidelines

ASPIRIN (IB) oral 150-325 mg or iv 250-

COX/TXA2 inhibitor
CLOPIDOGREL (IC)
P2Y12 receptor blocker
ABCIXIMAB (IIaA)
Glycoprotein receptor blocker
500 mg
oral loading preferably 600
mg
iv bolus 0.25 mg/kg than
0.125 µg/kg/min infusion
(max 10 µg/min for 12 hrs)
Three recently published/announced
trials on antiplatelet therapy in ACS

TRITON-TIMI 38
prasugrel vs clopidogrel (300/75 mg)
74% NSTEMI/UA

PLATO
ticagrelor vs clopidogrel (300 mg 59.5%, 600 mg 19.6%)
59.5% NSTEMI/UA

CURRENT OASIS-7
clopidogrel high (600/150/75) vs low dose (300/75 mg) + ASA high 300-325 mg)
vs low dose (75-100 mg)
70.8% NSTEMI/UA
 Metabolic Activation Pathway for
Clopidogrel and Prasugrel
CYP3A O
O CYP1A2 O CYP2C9 OCH3
OCH3 OCH3
CYP2C19 CYP2C19
CYP2B6 CYP2B6 HOOC N
N O N
HS Cl
S Cl S Cl
Es R-130964
Clopidogrel te 2-Oxo-clopidogrel
r as
e (active)
s
O OH

N
S Cl
SR26334
(inactive) CYP3A
O CYP2B6
O O
CYP2C9
O
Esterases N CYP2C19
N O HOOC N
H3 C O
S F S F F
HS
Prasugrel R-95913 R-138727
(inactive) (active)
CYP = cytochrome P-450
Rehmel JL, et al. Drug Metab Dispos 2006;34(4):600-607
 Inhibition of Platelet
Aggregation
Clopidogrel 300 mg Prasugrel 60 mg
100
20 µM ADP
* * *
* * *
80 *

60
IPA (%)

*
40

20

0
0 1 2 3 4 5 6 12 16 20 24
Time After Administration (h)
5 *p < 0.01; Mean ± SD Brandt JT et al. Am Heart J 2007;153(1):66.e9-16
Relative Risk and of Primary Endpoint Incidence in
Selected Subgroups
Hazard ratio for Prasugrel Prasugrel Clopidogrel% Reduction
N % in Risk (%)
(95% CI)
Overall 13608 9.9 12.1 19

Unstable angina/NSTEMI 10074 9.9 12.1 18

STEMI 3534 10.0 12.4 21
Sex
Male 10085 9.5 11.9 21
Female 3523 11.0 12.6 12
Age in years
< 65 8322 8.1 10.6 25
65-74 3477 10.7 12.3 14
> 75 1809 17.2 18.3 6
Diabetes mellitus
No 10462 9.2 10.6 14
Yes 3146 12.2 17.0 30
Stent type in index procedure
Bare-metal stent 6461 10.0 12.2 20
Drug-eluting stent 6383 9.4 11.6 18
Glycoprotein IIb/IIIa inhibitor use
Yes 7414 10.4 12.9 21
No 6194 9.3 11.0 16
Creatinine clearance (ml/min/1.73 m2)
< 60 1414 15.1 17.5 14
> 60 11485 9.0 11.1 20

Prasugrel Better Clopidogrel Better

Wiviott SD et al. N Engl J Med 2007;357(20):2001-2015
 TRITON-TIMI 38: STEMI Cohort Efficacy
Endpoints at 30 Days
12

10
* Clopidogrel
9.5 * *
8.8 8.8 Prasugrel
8 *
6.7 7.0
6.5
6.2
Patients (%)

6
4.9
4 * * p< 0.05
* *
2.6 2.4
2 1.9
1.6 1.3 1.2

0
CV Death/ CV Death/ CV Death/ All-cause NF MI UTVR Stent
NF MI/NF Stroke NF MI/UTVR NF MI Death Thrombosis†
†
Clinically adjudicated according to definite or probable Academic Research Consortium definitions
CV = cardiovascular; MI = myocardial infarction; NF = non-fatal; STEMI = ST-segment elevation myocardial
infarction; UTVR = urgent target vessel revascularisation
Montalescot G et al. Lancet 2009;373(9665):723-731
Prasugrel in combination with aspirin is recommended
as an option for preventing atherothrombotic events in
people with acute coronary syndromes having
percutaneous coronary intervention, only when:
• immediate primary percutaneous coronary intervention for
ST-segment-elevation myocardial infarction is necessary or

• stent thrombosis has occurred during clopidogrel treatment or

• the patient has diabetes mellitus

PCI in NSTEMI/UA – not before angiography? (CABG-related

bleeding!)

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL

EXCELLENCE
http://www.nice.org.uk/nicemedia/pdf/PrasugrelFADToPMForAppealPeriod.pdf
<>
 18
Recommendations for the use of
Thienopyridines, ACC/AHA 2009

MODIFIED
Recommendation

I IIa IIb III

Prasugrel 60 mg should be given as soon as
possible for primary PCI

I IIa IIb III

In patients receiving a stent (BMS or DES)
during PCI for ACS, clopidogrel 75 mg daily†
daily† or
prasugrel 10 mg§
mg§ daily should be givenfor at
least 12 months
 19
Thienopyridines

The duration of thienopyridine therapy

MODIFIED
Recommendation
should be as follows:

I IIa IIb III a. In patients receiving a stent (BMS or DES)

during PCI for ACS, clopidogrel 75 mg daily†
or prasugrel 10 mg§ daily should be given
for at least 12 months;

I IIa IIb III

b. If the risk of morbidity from bleeding
outweighs the anticipated benefit afforded
by thienopyridine therapy, earlier
discontinuation should be considered.
Ticagrelor (AZD6140)
PLATO Trial (2)
Ticagrelor Clopidorgel P
P. end point 9.8% 11.7% <0.001
MI 5.8% 6.9% 0.005
Death vascular 4.0% 5.1% 0.001
Stroke 1.5% 1.3% 0.22
Stent Thr def+prob 2.2% 2.9% 0.02
Major bleeding TIMI 7.9% 7.7% 0.57
Intracranial bleeding 0.3% 0.2% 0.06
CABG-related major 5.3% 5.8% 0.32
bleeding TIMI
PLATO Trial (3)

Ticagrelor Clopidogrel P
Dyspnea 13.8% 7.8% <0.001
Syncope 1.1% 0.8% 0.08
Ventr. pauses≥3 5.8% 3.6% 0.01
sec (1st week)
 serum 11±22% 9±22% <0.001
creatinine 12m
 serum uric 15±52% 7±31% <0.001
acid 12m
 CURRENT OASIS-7 Study Design
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)

Planned Early (<24 h) Invasive Management with intended PCI

Ischemic ECG ∆ (80.8%) or ↑cardiac biomarker (42%)

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)
Angio 24,769
(99%)
PCI 17,232 No PCI 7,855 (30%)
(70%)

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

Compliance:

Clop in 1st 7d (median) 7d 7d 2d

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

Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)
Key Subgroup: PCI v No PCI
Mehta S, ESC 2009
 CURRENT OASIS-7: Negative Study for Both Prespecified
Primary Outcome Analyses

Clopidogrel Clopidogrel 600

Comparison Clopidogrel 300 mg /150 mg/75
N=25,087 mg/ 75 mg mg HR 95% CI P
CV Death/MI/Stroke 4.4 4.2 0.95 0.84-1.07 0.3
7

ASA Comparison* ASA ASA

N=25,087 75-100 mg 300-325 mg HR 95% CI P
CV Death/MI/Stroke 4.4 4.2 0.96 0.85-1.08 0.47

* Open label randomization to ASA low vs ASA high limits interpretation

Mehta S, ESC 2009
 Clopidogrel Double vs Standard Dose
Bleeding Overall Population

Clopidogrel
Standard Double Hazard 95% CI P
N=12579 N=1250 Ratio
8

TIMI Major1 0.95 1.04 1.09 0.85-1.40 0.50

CURRENT Major2 2.0 2.5 1.25 1.05-1.47 0.01
CURRENT Severe3 1.5 1.9 1.23 1.02-1.49 0.03
Fatal 0.11 0.13 1.15 0.56-2.35 0.71
ICH 0.05 0.03 0.67 0.19-2.37 0.53
RBC transfusion ≥ 2U 1.76 2.21 1.26 1.06-1.51 0.01
CABG-related Major 0.9 1.0 1.10 0.85-1.42 0.48
1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units
3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units
Mehta S, ESC 2009
 Clopidogrel: Double vs Standard Dose
Primary Outcome: PCI Patients
CV Death, MI or Stroke

Clopidogrel Standard

15% RRR
0.04

Clopidogrel Double
Cumulative Hazard
0.03
0.02

HR 0.85
95% CI 0.74-0.99
0.01

P=0.036
0.0

0 3 6 9 12 15 18 21 24 27 30
Days Mehta S, ESC 2009
BRAVE-3 Trial
 STEMI 2003 Registry Collaborators
Witkowski A et al: European Heart Journal 2009; 30: 1736–1743

Study group: 7193 pts undergoing pPCI in 38 centres in

2003 in Poland

All pts received pretreatment with 300 mg of aspirin,
992 pts (14%) received glycoprotein (GP) IIb/IIIa
inhibitors, 2690 pts (37%) were treated with 300 mg
loading dose of clopidogrel, and 1566 (22%) received
combined antiplatelet treatment with both GP IIb/IIIa
inhibitors and clopidogrel

Remaining 1945 pts (27%) did not receive GP IIb/IIIa
inhibitors or clopidogrel

Primary endpoint of the study was all-cause mortality
up to 1 year from STEMI.
STEMI 2003 Registry Collaborators
7193 pts undergoing pPCI in 38 centres in 2003 in Poland

Witkowski A et al: European Heart Journal 2009; 30: 1736–1743

STEMI 2003 Coll.
 bivalirudin
prasugrel

abciximab
 Use of Glycoprotein IIb/IIIa Receptor 40

Antagonists in STEMI
OR and 95% CI of
30-day Mortality
Study Name Year Statistics p-value Dead/Total
SM Abciximab
GPI

Valgimigli 2005 0.667 (0.11-4.09) 0.661 2/87 3/88

EVA-AMI 2007 1.017 (0.36-2.86) 0.974 8/226 7/201
MULTISTRATEGY 2008 0.438 (0.13-1.44) 0.173 4/372 9/372
FATA 2008 1.367 (0.43-4.35) 0.596 7/351 5/341
0.843 (0.46-1.55) 0.584

0.1 0.2 0.5 1 2 5

Favors SM GPI Favors
Abciximab

Grum et al. Small Molecule GP IIb/IIIa

Inhibitors primary PCI.Circ Cardiovas
Intervent. 2009;2:230-2236.
 Use of Glycoprotein IIb/IIIa Receptor 41

Antagonists in STEMI
Modified
Recommendation

It is reasonable to start treatment with glycoprotein

IIb/IIIa receptor antagonists at the time of primary
PCI (with or without stenting) in selected patients
I IIa IIb III with STEMI:

abciximab

I IIa IIb III

tirofiban and eptifibatide

 42
Use of Glycoprotein IIb/IIIa Receptor
Antagonists in STEMI
Modified
Recommendation

The usefulness of glycoprotein IIb/IIIa receptor

I IIa IIb III antagonists (as part of a preparatory pharmacologic
strategy for patients with STEMI prior to arrival in
the cardiac catheterization laboratory for
angiography and PCI) is uncertain.
 Adjunctive antiplatelet therapy in primary PCI
for STEMI
Take-home message (1)
When Loading dose Maintanence dose (mg)
(mg)

Aspirin as soon as possible oral 150-325 mg 75-100 mg/day

or iv 250-500
mg

Clopidogrel as soon as possible 600 75 mg/day

150 for 7 days, than 75 mg
daily possible?
Prasugrel as soon as possible 60 10
Abciximab at the time of pPCI standard dose NA
preferred (IIaA) replaced by bivalirudin or
new P2Y12 blockers?
Eptifibatide/Tirofiban at the time of pPCI double bolus for NA
possible (IIaB AHA, eptifibatide
IIbB/C ESC) higher dose for
tirofiban (?)
A. Witkowski, ICI Tel Aviv 07.12.2009
The era of tailored antiplatelet therapy
is coming in STEMI patients!
Take-home message (2)

Antiplatelet therapy suited for individual patient

P2Y12 with higher and more predictable IPA (prasugrel)

Fast acting P2Y12 receptor blockers for urgent PCI in pts without
previous antiplatelet therapy

IIb/IIIa glicoprotein receptor blockers probably will gone (?) in

the era of selective, rapidly acting P2Y12 inhibitors and
bivalirudin

Reversible P2Y12 inhibitors (ticagrelor, elinogrel) will permit for

major surgery (CABG) on the same day

Effiacy vs safety considerations will be easier with multiple

antiplatelet agents with different safety/efficay profile available
A. Witkowski, ICI Tel Aviv 07.12.2009