Acute Coronary Syndrome:
Antiplatelets and Antithrombotics
Eduardo S. Caguioa, MD., FPCP, FPCC, FACC
Asst. Professor, UST Faculty of Medicine and Surgery, Dept of Medicine, Section of Cardiology
Medical Director, UST Hospital
Member of Advisory
Board:
• Astra-Zeneca
• MSD
• Pfizer
Disclosures
• Servier
Receives honorarium for
lectures or drug trials
Have no financial interest
in any drug company.
Milestones in ACS Management
Anti-Thrombin Rx
Heparin
[ Fondaparinux ]
Bivalirudin
LMWH
Anti-Platelet Rx
GP IIb/IIIa
blockers
Aspirin
Clopidogrel
Treatment Strategy
Conservative
Early invasive
PRISM-PLUS
PURSUIT
ESSENCE
1994
PCI
1995
~ 5% stents
ICTUS
REPLACE 2
OASIS-5
CURE
1997
1998 1999
2000 2001
~85% stents
2002
2003
2004
Drug-eluting stents
Ischemic risk
Bleeding risk
ACUITY
SYNERGY
TACTICS TIMI-18
1996
ISAR-REACT 2
Adapted from and with the courtesy of Steven Manoukian, MD
2005
2006
Evolution of ACS Therapies
Low molecular
weight heparin
DABIGATRAN
CLOPIDOGREL
IIb/IIIa receptor
antagonist
Atorvastatin
Fondaparinux
Bivalirudin
Aspirin
Heparin
Integrated
strategy
Early invasive management
1990
1996
1997
2000
2001
2005
2007
2008
Year
Adapted from White HD et al. Lancet 2008; 372: 570–84
Proportional effects of antiplatelet therapy on
Vascular events in five main high risk categories
Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
Absolute effects of antiplatelet therapy on
vascular events in five main high risk categories
Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
Clopidogrel in NSTE ACS: CURE
12,563 Pts, GP IIb/IIIa & early invasive approach discouraged
0.14
Placebo
(11.4%)
0.12
CV Death, MI, Stroke
0.10
Clopidogrel
(9.3%)
0.08
0.06
RR 0.80, p<0.001
0.04
0.02
0.0
0
3
6
Months of follow-up
CURE. NEJM 2001;345:494-502
9
12
Cumulative Hazard Rate
CURE: Very Early Efficacy of
Clopidogrel in NSTE ACS
CV Death, MI, Stroke, Severe Ischemia
Within First 24 Hours
0.025
34%
0.020
Relative
Risk
Reduction
Placebo
+ Aspirin
(n=6303)
0.015
0.010
P=.003
Clopidogrel
+ Aspirin
(n=6259)
0.005
0.0
0
2
4
6
8
10
12
14
16
18
Hours After Randomization
Yusuf S et al. Circulation 2003;107:966-972
20
22
24
Clopidogrel in STEMI
Double-blind, randomized, placebo-controlled trial in
3491 patients, age 18-75 yrs with STEMI < 12 hours
Fibrinolytic, ASA, Heparin
randomize
Clopidogrel
300 mg + 75 mg qd
Placebo
Study
Drug
Coronary Angiogram
(2-8 days)
Open-label
clopidogrel
per MD in
both groups
30-day clinical follow-up
Primary endpoint:
Occluded
artery (TIMI Flow Grade 0/1)
or D/MI by time
of angio
15
10
Clopidogrel
Odds Ratio 0.80
(95% CI 0.65-0.97)
P=0.026
0
5
20%
10
15.0
Placebo
5
20
36% 
P<0.0001
21.7
CV Death, MI, or Urg Revasc (%)
Occluded Artery or Death/MI (%)
25
in STEMI
15
Clopidogrel
0
Clopidogrel
Placebo
0
5
10
Sabatine MS et al. NEJM 2005; 352: 1179
15
days
20
25
30
PCI-CLARITY Design
3491 Patients Randomized
into CLARITY-TIMI 28
1752 assigned clopidogrel
300 mg  75 mg/d
(CLOPIDOGREL PRETREATMENT)
Open-label
clopidogrel w/
loading dose
recommended
1739 assigned placebo
(NO PRETREATMENT)
A n g i o g r a p h y
933 underwent PCI
during index hosp.
930 underwent PCI
during index hosp.
30-day clinical follow-up
Odds Ratio 0.54
No Pretreatment – 6.2%
(95% CI 0.35-0.85)
6
P=0.008
4
46%
2
Clopidogrel – 3.6%
Pretreatment
Sabatine MS et al. JAMA 2005;294:1224-32
0
Percentage with outcome (%)
8
CV Death, MI, or Stroke
following PCI
0
10
Days post PCI
20
30
Meta-Analysis of Clopidogrel Pretreatment
MI before PCI (%)
Clopidogrel
Pretreatment
No
Pretreatment
PCI-CURE
3.6
5.1
CREDO
n/a
n/a
PCI-CLARITY
4.0
6.1
Overall
3.7
5.5
Trial
Favors
Pretreatment
Favors
No Pretreatment
OR 0.67
P=0.005
CV Death or MI after PCI (%)
Trial
Clopidogrel
Pretreatment
No
0.25
Pretreatment
PCI-CURE
2.9
4.4
CREDO
6.0
7.1
PCI-CLARITY
3.3
5.4
Overall
3.9
5.5
0.5
1.0
OR (95% CI)
2.0
OR 0.71
P=0.004
Sabatine MS et al. JAMA 2005;294:1224-32
0.25
0.5
1.0
OR (95% CI)
2.0
20
Variable and Unpredictable
Response to Clopidogrel
Patients (%)
20
24 hrs after 300 mg Clopidogrel
N = 96, Elective PCI
“Resistance” = 31%
10
≤ -30
(-20,-10)
(-30,-20)
(-10,0)
(0,10)
(20,30)
(10,20)
(40,50)
(30,40)
>60
(50,60)
 Platelet aggregation before and after Clopidogrel (%)
“Resistance” = ≤ 10%  platelet aggregation
2015.01
Gurbel PA et al. Circulation 2003; 107: 2908-2913
21
Clopidogrel Response Variability and
Increased Risk of Ischemic Events
Primary PCI for STEMI (N = 60)
5 µM ADP induced plt agg
120
Clop resist
100
40
40
Q1
80
Q2
60
Q3
40
Q4
20
P = 0.007
30
Percent
Baseline (%)
Death/ACS/CVA by 6 m
20
10
6.7
Quartiles of response
0
1
2
3
4
Days
5
6
0
Q1
Q2
0
0
Q3
Q4
Matetzky S, et al. Circulation. 2004;109:3171-3175.
Wiviott SD, Antman EM. Circulation. 2004 109:3064-3067.
3116.01
Evolution of ACS Therapies
Low molecular
weight heparin
CLOPIDOGREL
Atorvastatin
PRASUGREL
IIb/IIIa receptor
antagonist
Fondaparinux
Bivalirudin
Aspirin
Heparin
Integrated
strategy
Early invasive management
1990
1996
1997
2000
2001
2005
2007
2008
Year
Adapted from White HD et al. Lancet 2008; 372: 570–84
More Efficient and Less Variable Activation of
Prasugrel Compared to Clopidogrel
Prasugrel
Clopidogrel
hCE1
85%
Inactive
Metabolite
Liver
CYP1A2,
2B6, 2C19
Gut
hCE2
Intermediate
Intermediate
Gut
Liver
CYP3A, 2B6,
2C9, 2C19
and
CYP3A, 2B6,
2C9, 2C19
Liver
Active Metabolite
CYP2C19 variants and inhibitors
affect the PK and PD of clopidogrel
Active Metabolite
Prasugrel has no clinically relevant
interactions with CYP2C19 variants or
inhibitors
Higher Active Metabolite Concentrations of
Prasugrel After Loading Dose
Active Metabolite Concentration
(ng/mL)
600
Cmax and Tmax influence onset of platelet inhibition
• Relevant for loading dose but not maintenance dose
AUC influences extent of platelet inhibition
• Relevant for loading and maintenance dose
500
400
Prasugrel 60 mg LD
300
Clopidogrel 600 mg LD
Clopidogrel 300 mg LD
100
0
0
2
Time (Hrs)
4
6
8
Prasugrel 60 mg LD with 10 mg MD Demonstrates
Superior Response Compared to Clopidogrel
60
52%
(%)
Non Responders
50
Loading dose
40
Maintenance dose
45%
36%
30
21%
20
10
3%
0
Pras
40 mg
3%
Pras
Clop
60 mg 300 mg
Day 1 (4 hr)
Pras
5 mg
0%
0%
Pras
Pras
Pras
7.5 mg
10 mg
15 mg
Day 28 (0 hr)
Clop
75 mg
Jernberg et al., Eur Heart J 2006; 27:1166-1173
TRITON-TIMI 38 Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
N = 13,608
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, stroke
CV death, MI, stroke, rehosp-Rec Isch
CV death, MI, UTVR
Stent thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, life-threatening bleeds
Key substudies: Pharmacokinetic, genomic
Balance of Efficacy and Safety: All ACS
15
Clopidogrel
12.1%
Endpoint (%)
CV death / MI / stroke
10
9.9%
Prasugrel
5
TIMI major
Non-CABG bleeds
Prasugrel
Clopidogrel
2.4%
1.8%
0
0
30 60 90
180
270
360
450
138
events
HR 0.81
(0.73 - 0.90)
P = 0.0004
NNT = 46
35
events
HR 1.32
(1.03 - 1.68)
P = 0.03
NNH = 167
Days
Wiviott SD et al. NEJM 2007; 357: 2001-2015
Antiplatelet Therapy in ACS
ASA
100
ASA + Clopidogrel
ASA +
Prasugrel
Ischemic events
- 22%
Reduction
in
Ischemic
Events
- 20%
- 19%
+ 60%
+ 38%
0
Placebo
APTC
Single
Antiplatelet Rx
CURE
Dual
Antiplatelet Rx
Increase
in
+ 32% Major
Bleeds
TRITON-TIMI 38
Higher
IPA
Wiviott SD et al. NEJM 2007; 357: 2001-2015
Net Clinical Benefit in Subgroups:
Death / MI / CVA / Major Bleed
Post-Hoc Analysis
Prior
TIA / stroke
Risk (%)
+ 54
Yes
No
Pint = 0.006
≥ 75 yrs
-16
-1
Age
< 75 yrs
Weight
Pint = 0.18
< 60 kg
+3
≥ 60 kg
Pint = 0.36
-14
-13
OVERALL
0.5
-16
Favors
Prasugrel
1
HR
Favors
Clopidogrel
2
Wiviott SD et al. NEJM 2007; 357: 2001-2015
Balance of Efficacy and Safety in Patients
< 75 Yrs, ≥ 60 kg, and without Prior TIA/Stroke
16
CV death, NF MI, or NF stroke
14
Clopidogrel 11.0%
Endpoint (%)
12
10
Hazard Ratio, 0.75
(95% CI, 0.66 - 0.84)
P < 0.001
8
Prasugrel 8.3%
6
4
TIMI major bleeding
Hazard Ratio, 1.240
(95% CI, 0.91 - 1.69)
P = 0.17
2
Prasugrel 2.0%
Clopidogrel 1.50%
0
0
30
90
180
270
360
450
Days
Modified from Wiviott SD et al. NEJM 2007; 357: 2001-2015
Kaplan-Meier estimates of the incidence of the primary
composite endpoint and of non-CABG related TIMI Major
bleeding for All ACS patients with diabetes.
All ACS
Patients with Diabetes
KM Estimates of Event Rate (%)
20
Clopidogrel
17.0%
CV Death, NF MI , or NF Stroke
15
Hazard Ratio, 0.705
(95% CI, 0.58-0.85)
p<0.001
10
Prasugrel
12.2%
Prasugrel
2.6%
Clopidogrel
2.5%
5
TIMI Major Bleeding
0
0
30
90
180
270
360
Days From Randomization or First Dose
450
Hazard Ratio, 1.06
(95% CI, 0.66-1.69)
p=0.81
Therapeutic Considerations
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Wiviott SD et al. NEJM 2007; 357: 2001-2015
Aspirin
Clopidogrel
Prasugrel
?
August 30, 2009
TICAGRELOR:
First and Only Approved CPTP
 TICAGRELOR, a new chemical class,
is a cyclo-pentyl-triazolo-pyrimidine
(CPTP)
 Ticagrelor is direct acting (not a prodrug and does not require metabolic
activation)
 It binds directly to P2Y12 receptors
and reversibly interacts with the
receptor,
to
prevent
platelet
activation and aggregation
 Thienopyridines bind covalently to
P2Y12 ADP binding site for the life of
the platelet
Husted S, et al. Eur Heart J. 2006;27:1038–1047.
Gurbel PA, et al. Expert Opin Drug Metab Toxicol. 2009;5(8):989–1004.
Van Giezen JJ, et al. J Thromb Haemost. 2009;7:1556-1565.
ADP binding
site
Ticagrelor
P2Y12
receptor
on platelet
Inhibition of Platelet Aggregation: Onset
Inhibition of Platelet Aggregation
100
*
Ticagrelor (n=54)
*
*
*
*
80
Clopidogrel (n=50)
60
*
40
Placebo (n=12)
20
0
0
2
Loading Dose
4
6
8
10
12
14
16
18
20
22
24
Time (Hours)
Ticagrelor 180-mg loading dose in Stable CAD patients
Clopidogrel 600-mg loading dose in Stable CAD patients
*P<0.0001Ticgrelor vs Clopidogrel
Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585.
PLATO: Study Design
18,624 patients with ACS
(UA, NSTEMI, or STEMI*)
randomized within 24
hours of symptom onset
Initial treatment approaches
• Medically managed (n=5,216 — 28.0%)
• Invasively managed (n=13,408 — 72.0%)
Patients could be taking clopidogrel at
time of randomization
Ticagrelor (n=9,333)
Clopidogrel (n=9,293)
300-mg loading dose†
75 mg qd + ASA Maintenance dose
180-mg loading dose
90 mg bid + ASA Maintenance dose
6–12 months of double-blind treatment
Primary efficacy endpoint:
Primary safety endpoint:
Composite of CV death, MI
(excluding silent MI), or stroke
Total PLATO major bleeding‡
*STEMI patients scheduled for primary PCI were randomized; 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.
1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
2. James S, et al. Am Heart J. 2009;157:599–605.
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
 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)
James S, et al. Am Heart J. 2009;157:599–605.
PLATO: Baseline Characteristics
TICAGRELOR
(n=9,333)
Clopidogrel
(n=9,291)
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)
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)
MI
1,900 (20.4)
1,924 (20.7)
PCI
1,272 (13.6)
1,220 (13.1)
532 (5.7)
574 (6.2)
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)
7,965 (85.3)
7,999 (86.0)
Characteristic
Median age, years
CV risk factors, n (%)
History, n (%)
CABG
ECG at study entry, n (%)
Troponin-I positive, n (%)
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Cumulative Incidence (%)
PLATO: Primary Efficacy Endpoint
(Composite of CV Death, MI, or Stroke)
13
12
11
10
9
8
7
6
5
4
3
2
1
0
0–30 Days
0–12 Months
11.7 Clopidogrel
9.8
TICAGRELOR
Clopidogrel
5.4
4.8
TICAGRELOR
ARR=0.6%
ARR=1.9%
RRR=12%
RRR=16%
P=0.045
NNT=54*
HR: 0.88 (95% CI, 0.77−1.00)
P<0.001
HR: 0.84 (95% CI, 0.77–0.92)
0
2
4
6
8
10
12
Months After Randomization
No. at risk
TICAGRELOR
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel
9,291
8,521
8,362
8,124
6,650
5,096
4,047
Both groups included aspirin.
*NNT at one year.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
PLATO: Predefined Testing of Primary and
Major Secondary Efficacy Endpoints
TICAGRELOR
(n=9,333)
Clopidogrel
(n=9,291)
HR for TICAGRELOR
(95% CI)
P Value**
864 (9.8)
1,014 (11.7)
0.84 (0.77–0.92)
<0.001
901 (10.2)
1,065 (12.3)
0.84 (0.77–0.92)
<0.001
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‡
All Patients*
Primary endpoint, n (%/year)
Death from vascular cause + MI† + stroke
Secondary endpoints, n (%/yr)
Death from any cause + MI† + stroke
Death from vascular causes + MI† + stroke
+ severe recurrent ischemia + recurrent
ischemia + TIA + arterial thrombus
Nominal
Significance
* 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.
Both groups included aspirin.
The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
PLATO: Secondary Efficacy Endpoints
Cardiovascular Death
Myocardial Infarction
Clopidogrel
6
5.8
TICAGRELOR
5
4
3
ARR=1.1%
2
RRR=16%
Calculated NNT=91
1
7
Cumulative Incidence (%)
Cumulative Incidence (%)
7
6.9
6
Clopidogrel
4.0
4
TICAGRELOR
3
ARR=1.1%
2
RRR=21%
NNT=91
1
P=0.005
P=0.001
HR: 0.84 (95% CI, 0.75–0.95)
2
4
6
8
10
Months After Randomisation
HR: 0.79 (95% CI, 0.69–0.91)
0
0
0
5.1
5
12
0
2
4
6
8
Months After Randomisation
Rate of stroke for TICAGRELOR was not different from clopidogrel (1.3% vs 1.1% ), P=0.225.
Both groups included aspirin.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement.
BRILIQUE: Summary of Product Characteristics, 2010.
10
12
PLATO: Primary Safety Endpoint
PLATO-defined Total
Major Bleeding (%)
15
TICAGRELOR
Clopidogrel
10
11.6%
11.2%
5
P=0.43
HR: 1.04 (95% CI, 0.95–1.13)
0
0
60
120
180
240
300
360
Days From First Dose
No. at risk
TICAGRELOR
9,235
7,246
6,826
6,545
5,129
3,783
3,433
Clopidogrel
9,186
7,305
6,930
6,670
5,209
3,841
3,479
Both groups included aspirin.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
P=NS
PLATO: Bleeding
18
BRILINTA (n=9,235)
P = 0.008
K-M Estimated Rate (% Per Year)
16.1
16
Clopidogrel (n=9,186)
14.6
14
NS
12
11.6
11.2
10
NS
8
NS
5.8
6
7.4
5.8
4.5
4
2
NS
0.3
7.9
P = 0.03
3.8
0.3
0
Major Bleeding
Life-threatening/
Fatal Bleeding
Fatal Bleeding
All values presented by PLATO criteria.
Both groups included aspirin.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Major and Minor
Bleeding
Non-CABG-Major
Bleeding
CABG-Major
Bleeding
PLATO: Dyspnea
Dyspnoea in the PLATO trial
Ticagrelor
Clopidogrel
P Value
Incidence of dyspnea adverse events (%)
13.8
7.8
<0.001
Patients who discontinued treatment due to
dyspnoea (%)
0.9
0.1
<0.001
 Ticagrelor-associated dyspnea 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
 In 2.2% of patients, investigators considered dyspnoea causally related to treatment
with Ticagrelor
 Label precautions and warnings: use with caution in patients with history of asthma
and COPD
Ticagrelor: Summary of Product Characteristics, 2010.; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Storey R, et al. J Am Coll Cardio. 2010;55(Suppl 1):A108.E1007.
PLATO: Bradycardia-related Events
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186)
P Value
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
All Patients
Bradycardia-related event, n (%)
• 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)
• Label precautions and warnings: Ticagrelor should be used with caution in patients at risk
of bradycardic events
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.
PLATO: Laboratory Parameters
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186)
P Value
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
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
All Patients
Mean % increase (± SD) in serum creatinine from
baseline
Mean % increase (± SD) in serum uric acid from baseline
• Creatinine levels may increase during treatment with ticagrelor; renal function should be checked after 1
month and thereafter according to medical practice
• Label precautions and warnings: as a precautionary measure, the use of ticagrelor in patients with uric
acid nephropathy is discouraged
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.
Comparison of ticagrelor with clopidogrel in
patients with a planned invasive strategy for
acute coronary syndromes (PLATO): a
randomised double-blind study
Christopher P. Cannon, Robert A. Harrington, Stefan James, et al. for the
PLATelet inhibition and patient Outcomes (PLATO) investigators
 Presented at ESC 2009 as an oral presentation
 Subsequently published in Lancet, January 2010
 A pre-specified objective of PLATO was to compare outcomes of
Ticagrelol versus clopidogrel in patients with planned invasive strategy
at randomization
 For all patients, the intention for early invasive management had to be
indicated by the investigator before patients were randomized
Cannon CP, et al. Lancet. 2010;375:283−293.
PLATO Primary Endpoint: Initial Invasive vs Initial NonInvasive Management
Initial Non-Invasive
28% of patients in PLATO
10.7%
Clopidogrel
9%
Ticagrelor
P<0.0025
HR: 0.84 (95% CI, 0.75–0.94)
K-M Estimated Rate Primary
Composite of CV Death/MI/Stroke (%)
K-M Estimated Rate Primary
Composite of CV Death/MI/Stroke (%)
Initial Invasive
72% of patients in PLATO
16
14.3%
14
Clopidogrel
12%
12
10
Ticagrelor
8
6
4
P<0.045
2
HR: 0.85 (95% CI, 0.73–1.00)
0
0
Days After Randomisation
60
120
180
240
300
360
Days After Randomisation
No. at risk
Ticagrelor
6,732
6,236
6,134
5,972
4,889
3,735
3,048
Ticagrelor
2,601
2,392
2,326
2,247
1,854
1,426
1,099
Clopidogrel
6,676
6,129
6,034
5,881
4,815
3,680
2,965
Clopidogrel
2,615
2,392
2,328
2,243
1,835
1,416
1,109
James S, et al. ESC 2010; Poster #1353.; Cannon C, et al. Lancet. 2010;375:283–293.
Clinical Implications
 In ACS patients with planned invasive management at randomisation in
PLATO, compared with clopidogrel, ticagrelor significantly reduced the
incidence of
• CV death/MI/stroke (primary efficacy endpoint)
 Ticagrelol: 9.0% vs clopidogrel: 10.7%
• CV death
 Ticagrelol: 3.4% vs clopidogrel: 4.3%
 Consistent with the overall study, ticaggrelor had an increase in dyspnea
in this patient population compared to clopidogrel
 In PLATO, in ACS patients with a planned invasive management strategy,
Ticagrelol was shown to be more effective than clopidogrel for the
prevention of CV and total death without any significant increase in major
bleeding*
 Invasive study was consistent with the overall results from PLATO
* No overall increase in major bleeding in this sub-study, however there was an increase in the PLATO main non-CABG
bleeding (Ticagrelor: 4.5% vs. clopidogrel 3.8%); and major and minor bleeding (Ticagrelor16.1% vs. clopidogrel 14.6%).
European Association for Percutaneous Cardiovascular Intervention, et al. Eur Heart J. 2010;31:2501–2555.
Canadian Cardiovascular Society Anti Platelet Guidelines published online at http://www.ccs.ca. Accessed February 12, 2011.
Adapted form Cannon CP, et al. Lancet. 2010;375:283−293.
TICAGRELOR Indication
By Diagnosis
By Treatment
UA/NSTEMI
STEMI
Medical
management
PCI
CABG





 Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated
for the prevention of atherothrombotic events in adult patients with
acute coronary syndromes (unstable angina, non–ST-elevation
myocardial infarction [NSTEMI] or ST-elevation myocardial infarction
[STEMI]); including patients managed medically, and those who are
managed with percutaneous coronary intervention (PCI) or coronary
artery bypass grafting (CABG)
If clinically indicated, Ticagrelor should be used with caution in the following patient groups: Patients with concomitant
administration of medicinal products that may increase the risk of bleeding (eg, non-steroidal anti-inflammatory drugs
(NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing
Ticagrelor: Summary of Product Characteristics, 2010.
Aspirin
Clopidogrel
Prasugrel
Ticagrelor
?
New Anticoagulants in AF and ACS
Perspective:
1. The availability, of new treatment alternatives for stroke prevention in patients
with nonvalvular atrial fibrillation is a great step forward to further improve
outcomes and quality of life.
2. Compared with warfarin, these new alternatives have important advantages, with
their lower risk of intracranial bleeding, no clear interactions with food, fewer
interactions with medications, and no need for frequent laboratory monitoring
and dose adjustments.
3. Dabigatran etexilate is a synthetic low molecular weight peptidomimetic that
binds directly and reversibly to the catalytic site of thrombin.
4. Rivaroxaban, apixaban, and endoxaban are selective direct factor Xa inhibitors.
5. Based on the currently available results from the individual trials, it is clear that
both the oral direct thrombin inhibitor dabigatran etexilate and the oral factor Xa
inhibitors apixaban and rivaroxaban are attractive alternatives to warfarin or
aspirin in patients with nonvalvular atrial fibrillation and an increased risk of
stroke.
New Anticoagulants in AF and ACS
Perspective:
6. Apixaban 5 mg (with dose reduction to 2.5 mg in specific cases) BID is currently
the best documented alternative to both warfarin and aspirin for stroke
prevention in a broad population with atrial fibrillation and increased risk of
stroke, based on two independent large-scale trials. Apixaban is awaiting Food
and Drug Administration approval in the United States for atrial fibrillation.
7. Patients already on long-term vitamin K antagonist (VKA) treatment, with wellcontrolled international normalized ratio and handling VKA treatment and
laboratory monitoring without problems, derive uncertain overall advantages
from switching to the new oral anticoagulants, and the arguments for changing
treatment in such patients appear weak.
8. There is also a need for more information on how to manage patients with
bleeding because there are no specific antidotes for any of the new agents.
9. The cost of the drug at the patient level might be an obstacle to their use,
although the cost-effectiveness at a societal level might be tolerable in
comparison with other recently accepted novel treatments.
10. Additional trials are indicated to determine the utility of these agents in
combination with antiplatelet treatments after myocardial infarction and
percutaneous coronary intervention.
Thank you for your attention!