Role of More Potent Antiplatelet in ACS Management

The Standard Dual Antiplatelet
Therapy for ACS
Clopidogrel : loading dose 300 mg, followed
by 75 mg daily
ASA: 160 mg non-enteric chewed tablet,
followed by 80 mg daily

Trial & population Comparison Primary Endpoint Bleeding
CURE (2001)
NSTE-ACS patients
n = 12,562
Clopidogrel 75 mg
(300 mg loading)
vs. placebo
CV death, MI, CVA
Clopidogrel 9.3%
Placebo 11.4%
(P < 0.001)
ARR 2.1%;
RRR 20%; NNT 48
Major bleeding*
Clopidogrel 3.7%
Placebo 2.7%
(P = 0.001)
NNH: 100
PCI Cure (2001)
NSTE-ACS undergoing
PCI
n = 2,658
Like CURE (after PCI
clopidogrel in both
groups for 1 month)
CV death, MI, or
urgent TVR in
30 days
Clopidogrel 4.5%
Placebo 6.4%
ARR 1.9%;
RRR 30%; NNT 53
Major bleeding*
Clopidogrel 2.7%
Placebo 2.5%
(P = 0.69
CURRENT OASIS 7 (2010)
NSTE-ACS - 63%
STEMI - 37%
n = 25,086
Clopidogrel double
dose
(600 mg loading, 150
mg day 2–7, then 75
mg) vs. standard dose
75 mg (150 mg
loading)
CV death, MI, CVA
(at 30 days)
Double 4.2%
Standard 4.4%
(P = 0.30)
Major bleeding
Double 2.5%
Standard 2.0%
(P = 0.01)
NNH: 200
Clopidogrel Trials
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
* CURE Definition

Potential Limitations of
Clopidogrel
Moderate overall levels of platelet inhibition
Average IPA ~50%
High variability response within a population
4-34% with very low levels of platelet inhibition
Slow onset of antiplatelet effect
Requiring 300 – 600 mg loading doses in acute
phase
Gurbel et al. Circulation 2009;120:2577-2585
O’ Donoghue M. Wiviott SD . Circulation 2006;114:e600-e606

Inhibition of ADP-Induced Platelet Function Following 600mg Clopidogrel in 1,001 patients
Hochholzer W. Circulation 2005;111: 2560-2564
Variability in Clopidogrel
Responsiveness

Angiolillo DJ & Ueno M. JACC: Cardiology Interventions 2011;4 (4):411–414

Trial & population Comparison Primary Endpoint Bleeding
TRITON (2007)
Undergoing PCI
NSTE-ACS 74%
STEMI 26%
n = 13 608
Prasugrel 10 mg
(60 mg loading)
vs. clopidogrel
75 mg
(300 loading)
CV death, MI, CVA
Prasugrel 9.9%
Clopidogrel 12.1%
(P < 0.001)
ARR 2.2%;
RRR 27%;
NNT 45
Non–CABG-related
major bleeding:#
Prasugrel 2.4%
Clopidogrel 1.8%
(P = 0.03)
NNH: 167
CABG-related major
bleeding Prasugrel
13.4%
Clopidogrel 3.2%
(P < 0.001)
NNH: 10 (CABG
Prasugrel Trial
* TIMI Criteria

Ticagrelor is a cyclo-pentyl-
triazolo-pyrimidine (CPTP)
OH
OH
O
OH
N
F
S
N
H
N
N
N
N
F
• Direct-acting
– Not a pro drug: does not require metabolic activation
– Rapid onset of inhibitory effect on the P2Y12 receptor than clopidogrel
• Reversibly bound
– Faster offset than clopidogrel
– Functional recovery of circulating platelets within ~ 48 hours
Ticagrelor
Deeks ED. Drugs 2011;71(7):909-933
Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274

Adapted from Schomig A. N Engl J Med. 2009;361:1108–1111.
Ticagrelor:
Does NOT require metabolic activation to
become active drug
Clopidogrel:
A prodrug; requires metabolism to
become active drug
CYP-dependent
oxidation
CYP1A2
CYP2B6
CYP2C19
CYP-dependent
oxidation
CYP2C19
CYP3A4/5
CYP2B6
Active compound
Intermediate metabolite
Prodrug
Ticagrelor
Clopidogrel
Binding
P2Y12
Ticagrelor: Does Not Require Hepatic
Metabolism for Activation
Platelet

Ticagrelor P2Y12 receptor
binding
ADP, adenosine diphosphate
Adapted from Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274
ADP
P2Y12 receptor ADP binds and activates
the receptor
Conformational change
and signalling
Ticagrelor binds away
from ADP pocket
ADP can bind reversibly
but no conformational
change or signalling
Receptor remains intact
upon dissociation

ONSET/OFFSET: Pharmacodynamics in
Stable CAD Patients
Onset
100
90
80
70
60
50
40
30
20
10
0
IPA%
//
Ticagrelor (n=54)
Clopidogrel (n=50)
0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240
Maintenance Offset
Time (Hours)
Loading
Dose
180 mg
600 mg
*
*
* * *
‡
†
** †
Last
Maintenance
Dose
90 mg bid
75 mg qd
//
*
*
//
* P<0.0001
† P<0.005
‡ P<0.05
Time (Hours)
Gurbel PA et al. Circulation 2009;120:2577-2585

PLATO Study
PLATO Study2:
• 43 countries
• 862 sites
• 18,624 patients
43 countries862 sites
PLATO study tested the hypothesis that…
ticagrelor will result in a lower risk of recurrent thrombotic events in a broad
patient population with ACS as compared to clopidogrel and this would be
achieved with a clinically acceptable bleeding rate and overall safety profile1
18,624 patients
1. James S et al. Am Heart J 2009;157: 599 – 605
2. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

PLATO: Study Population
ACS Patient
STEMI
Primary PCI
No Reperf
Fibrinolytic Rx
UA/NSTEMI
Initial Invasive
Management
PCI
No revascularisation
CABG
Initial Non-Invasive
Management
PCI
CABG
No revascularisation
Only STEMI patients
intended for primary PCI
included
Adapted from James S, et al. Am Heart J. 2009;157:599–605.

180-mg loading dose
Ticagrelor (n=9,333)
*STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI.
†A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel,
with an additional 300 mg allowed at the discretion of the investigator.
‡The PLATO study expanded the definition of major bleeding to be more inclusive compared with
previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major
bleeding event.
90 mg bid + ASA maintenance dose
300-mg loading dose† 75 mg qd + ASA maintenance dose
Clopidogrel (n=9,291)
Primary efficacy
endpoint:
Composite of CV
death, MI (excluding
silent MI), or stroke
Primary safety
endpoint:
Total PLATO major
bleeding‡
N=18,624
Patients with ACS
(UA, NSTEMI, or
STEMI*)
<24h Month 1 Month 3 Month 6 Month 9 Month 12Screening
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6
Initial Treatment approaches
• Medically managed (n=5,216 — 28.0%)
• Invasively managed (n=13,408 — 72.0%)
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
James S, et al. Am Heart J. 2009;157:599–605.
Randomisation
• All patients were hospitalised with symptom onset <24 hours
• Patients could be taking clopidogrel at time of randomisation
PLATO: Study Design

PLATO Main: Inclusion Criteria
• Hospitalisation for STEMI or NSTEMI/UA ACS, with
onset during previous 24 hours
• With STEMI, the following 2 inclusion criteria were
required
– Persistent ST elevation of at least 0.1 mV in ≥2
contiguous leads or new LBBB
– Primary PCI planned

PLATO Main: Inclusion Criteria
• With NSTEMI, at least 2 of the following 3 were required
– ST changes on ECG indicating ischaemia
– Positive biomarker indicating myocardial necrosis
– One of the following risk indicators
• ≥60 years of age
• Previous MI or CABG
• CAD with ≥50% stenosis in ≥2 vessels
• Previous ischaemic stroke, TIA, carotid stenosis (≥50%), or
cerebral revascularisation
• Diabetes mellitus
• Peripheral artery disease
• Chronic renal dysfunction (creatinine clearance <60 mL/min)

PLATO Main: Key Exclusion Criteria
• Contraindication to clopidogrel
• Fibrinolytic therapy within 24 hours
• Oral anticoagulation therapy that cannot be stopped
• ACS event was a complication of previous PCI
• PCI after index event (initial clinical signs and symptoms)
and before first study dose
• Increased risk for bradycardic events
• Concomitant therapy with strong CYP3A
inhibitors/inducers
• Patients requiring dialysis

PLATO: Baseline Characteristics
Characteristic
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
Median age, years 62.0 62.0
Age ≥75 years, n (%) 1,396 (15.0) 1,482 (16.0)
Women, n (%) 2,655 (28.4) 2,633 (28.3)
CV risk factors, n (%)
Habitual smoker 3,360 (36.0) 3,318 (35.7)
Hypertension 6,139 (65.8) 6,044 (65.1)
Dyslipidemia 4,347 (46.6) 4,342 (46.7)
Diabetes mellitus 2,326 (24.9) 2,336 (25.1)
History, n (%)
MI 1,900 (20.4) 1,924 (20.7)
PCI 1,272 (13.6) 1,220 (13.1)
CABG 532 (5.7) 574 (6.2)
ECG at study entry, n (%)
ST-segment elevation, persistent 3,497 (37.5) 3,511 (37.8)
ST-depression 4,730 (50.7) 4,756 (51.2)
T-wave inversion 2,970 (31.8) 2,975 (32.0)
Troponin-I positive, n (%) 7,965 (85.3) 7,999 (86.0)

Both groups included aspirin.
*NNT at one year.
PLATO: Primary Efficacy Endpoint
(Composite of CV Death, MI, or Stroke)
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
Months After Randomization
8,521
8,628
8,362
8,460
8,124 6,650
6,743
5,096
5,161
4,047
4,1478,219
0 2 4 6 8 10 12
12
11
10
9
8
7
6
5
4
3
2
1
0
13CumulativeIncidence(%)
11.7 Clopidogrel
9.8 Ticagrelor
ARR=0.6%
RRR=12%
P=0.045
HR: 0.88 (95% CI, 0.77−1.00)
0–30 Days
4.8
5.4
Clopidogrel
Ticagrelor
ARR=1.9%
RRR=16%
NNT=54*
P<0.001
HR: 0.84 (95% CI, 0.77–0.92)
0–12 Months

PLATO: Predefined Testing of Primary and
Major Secondary Efficacy Endpoints
All Patients*
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
HR for Ticagrelor
(95% CI)
P Value**
Primary endpoint, n (%/year)
Death from vascular cause + MI† + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001
Secondary endpoints, n (%/yr)
Death from any cause + MI† + stroke 901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92) <0.001
Death from vascular causes + MI† + stroke
+ severe recurrent ischemia + recurrent
ischemia + TIA + arterial thrombus
1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95) <0.001
MI† 504 (5.8) 593 (6.9) 0.84 (0.75–0.95) 0.005
Death from vascular causes 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.001
Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.22
Death from any cause 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001‡
Nominal
Significance
The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months.
* Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded
from the CV death category. ** By Cox regression analysis using treatment as factor; †Excluding silent MI; ‡Death from any cause was tested after
stroke, which was non-significant, so the results should be considered nominally significant.

Months After Randomisation
0 2 4 6 8 10 12
6
5
4
3
2
1
0
7
CumulativeIncidence(%)
Clopidogrel
Ticagrelor
5.8
6.9
0 2 4 6 8 10 12
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
7
5
Months After Randomisation
Myocardial Infarction Cardiovascular Death
CumulativeIncidence(%)
PLATO: Secondary Efficacy Endpoints
Rate of stroke for Ticagrelor was not different from clopidogrel (1.3% vs 1.1% ), P=0.225.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement.
ARR=1.1%
RRR=16%
Calculated NNT=91
P=0.005
HR: 0.84 (95% CI, 0.75–0.95)
ARR=1.1%
RRR=21%
NNT=91
P=0.001
HR: 0.79 (95% CI, 0.69–0.91)

PLATO Primary Endpoint: Initial Invasive vs
Initial Non-Invasive Management
James S, et al. ESC. 2010; Poster #1353.
Cannon CP, et al. Lancet. 2010;375:283–293.

Stent Thrombosis ticagrelor vs clopidogrel
0,6%
ARR
33%
RRR
P = 0.009
Ticagrelor
n= 5640
Clopidogrel
n = 5649
Wallentin L, et al. N Engl J Med 2009;361:1045-57
* Definition by Academic Research Consortium criteria

PLATO Efficacy Results
Summary
Ticagrelor significantly reduced the composite of
CV death, MI or stroke vs clopidogrel at 1 year
(1.9% ARR, 16% RRR, P<0.001, NNT=54)
Ticagrelor significantly reduced CV mortality vs
clopidogrel
(1.1% ARR, 21% RRR, P=0.001)
Risk of CV death and MI were both significantly reduced
Risk of stroke was not significantly different
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

PLATO Efficacy Results
Summary
The absolute risk reduction with ticagrelor vs
clopidogrel starts early and continues to build
over the full 1 year treatment period
For every 91 ACS patients treated with
ticagrelor for 1 year, instead of clopidogrel, 1
CV death was prevented (NNT=91)
The effect of ticagrelor over clopidogrel
appears consistent across many subgroups

P=0.43
HR: 1.04 (95% CI, 0.95–1.13)
PLATO: Primary Safety Endpoint
PLATO-definedTotal
MajorBleeding(%)
Days From First Dose
10
5
0
15
0 60 120 180 240 300 360
Clopidogrel
Ticagrelor
11.2%
11.6%
P=NS
No. at risk
Clopidogrel
Ticagrelor
9,186
9,235
7,305
7,246
6,930
6,826
6,670 5,209
5,129
3,841
3,783
3,479
3,4336,545

PLATO: Safety Endpoints - bleeding
*Both groups included aspirin; **Proportion of patients (%)

PLATO: Bleeding
11.6
5.8
0.3
16.1
4.5
7.4
11.2
5.8
0.3
14.6
3.8
7.9
0
2
4
6
8
10
12
14
16
18
BRILINTA(n=9,235)
Clopidogrel(n=9,186)
All values presented by PLATO criteria.
Major Bleeding Non-CABG-
Major Bleeding
Major and
Minor Bleeding
Life-threatening/
Fatal Bleeding
Fatal Bleeding CABG-Major
Bleeding
K-MEstimatedRate(%PerYear)
NS
P = 0.03
P = 0.008
NS
NS
NS

PLATO: Dyspnoea
• Ticagrelor-associated dyspnoea was mostly mild to moderate in severity
and did not reduce efficacy
• Most events were reported as single episode occurring early after starting
treatment
• Not associated with new or worsening heart or lung disease
BRILINTA. Indonesia Prescribing Information 2012.
Storey R, et al. Eur Heart J 2011;32:2945-2953
Dyspnoea in the PLATO trial Ticagrelor Clopidogrel P Value
Incidence of dyspnoea adverse events (%) 13.8 7.8 <0.001
Patients who discontinued treatment due to
dyspnoea (%)
0.9 0.1 <0.001

PLATO: Bradycardia-related Events
All Patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) P Value
Bradycardia-related event, n (%)
Pacemaker insertion 82 (0.9) 79 (0.9) 0.87
Syncope 100 (1.1) 76 (0.8) 0.08
Bradycardia 409 (4.4) 372 (4.0) 0.21
Heart Block 67 (0.7) 66 (0.7) 1.00
• Ventricular pauses ≥3 seconds occurred in 5.8% of Ticagrelor-treated patients vs 3.6% of
clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively
• There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope,
bradycardia, and heart block)
1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.2. Scirica BM et al. J Am Coll Cardiol 2011;57:1908-1916
3. BRILINTA Indonesia Prescribing Information 2012.

PLATO: Laboratory Parameters
All Patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) P Value
Mean % increase (± SD) in serum creatinine from
baseline
At 1 month 10 ± 22 8 ± 21 <0.001
At 12 months 11 ± 22 9 ± 22 <0.001
1 month after end of treatment 10 ± 22 10 ± 22 0.59
Mean % increase (± SD) in serum uric acid from
baseline
At 1 month 14 ± 46 7 ± 44 <0.001
At 12 months 15 ± 52 7 ± 31 <0.001
1 month after end of treatment 7 ± 43 8 ± 48 0.56

CI, confidence interval; CrCl, creatinine clearance; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
James S, et al. Circulation 2010;122:1056–1067.
Renal function and outcomes in PLATO: Primary
composite endpoint by CrCl
Ticagrelor
better
Clopidogrel
better
Risk of CV death, stroke or MI
HR (95% CI)
30
40
50
60
70
80
90
100
CrCl
(mL/min)
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.20.4
Increasingrenalimpairment

PLATO Safety Results
Summary
No increase in overall major bleeding with
Ticagrelor vs clopidogrel
Non-CABG major bleeding and major + minor
bleeding were more frequent withTicagrelor
vs clopidogrel
No increase in overall fatal/life-threatening
bleeding withTicagrelor vs clopidogrel

PLATO Safety Results
Summary
There are more dyspnoea-related events
associated withTicagrelor vs clopidogrel,
however most events were mild to moderate
in intensity and often resolved without a need
for treatment

Implicating New Guidelines into ACS
Management

ESC Guidelines for the management of ACS in patients
presenting without persistent ST-segment elevation

LevelClass
Steg PG, et al. European Heart Journal. 2012;33:2569-2619
Oral antiplatelet in ESC
2012 STEMI Guideline

ACCF/AHA 2013 STEMI
Guideline
Anderson JL, et al.Circulation. 2007;116:e148-e304.

Summary
Ticagrelor is an active drug with reversible
binding to P2Y12 receptor
Ticagrelor provide fast onset and fast offset
Ticagrelor significantly reduces the combined
risk of CV death, MI, or stroke as compared to
clopidogrel in patients with ACS

Summary
Ticagrelor is effective in a broad spectrum of
ACS patients
There is no increase of overall major bleeding
withTicagrelor as compared to clopidogrel
Ticagrelor has been recommended in ACS
guidelines both in initial management ,
before PCI procedure and at discharge

Role of More Potent Antiplatelet in ACS Management

Role of More Potent Antiplatelet in ACS Management

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