1) The PLATO trial compared ticagrelor to clopidogrel for prevention of cardiovascular events in patients with acute coronary syndromes. It involved over 18,000 patients across 43 countries. 2) The primary endpoint was a composite of death from vascular causes, myocardial infarction, or stroke. At 12 months, this occurred in 9.8% of ticagrelor patients compared to 11.7% of clopidogrel patients, showing ticagrelor was more effective at reducing cardiovascular events. 3) The primary safety endpoint of major bleeding at 12 months occurred in 11.6% of ticagrelor patients and 11.2% of clopidogrel patients, showing no significant

1. Ticagrelor compared with clopidogrel
in patients with acute coronary
syndromes – the PLATO trial
PRESENTER:-HABIBUR RAHAMAN,1ST
YEAR PGT
CHAIRPERSON:-DR.PIJUSH KANTI
BISWAS,ASSOCI.PROF,GENERAL
MEDICINE,NRSMCH,KOLKATA,WB,IND

2. August 30, 2009 at 08.00 CET

3. Ticagrelor (AZD 6140):
an oral reversible P2Y12 antagonist
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 prodrug; does not require metabolic activation
– Rapid onset of inhibitory effect on the P2Y12 receptor
– Greater inhibition of platelet aggregation than clopidogrel
• Reversibly bound
– Degree of inhibition reflects plasma concentration
– Faster offset of effect than clopidogrel
– Functional recovery of all circulating platelets

4. PLATO background
• In NSTE-ACS and STEMI, current guidelines
recommend 12 months aspirin and clopidogrel
• Efficacy of clopidogrel is hampered by
– slow and variable transformation to the active metabolite
– modest and variable platelet inhibition
– increased risk of bleeding
– risk of stent thrombosis and MI in poor responders
PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation;
STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction

5. PLATO study design; Phase III, Multi-centered,
double-blinded, randomized controlled trial
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
6–12-month exposure
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack

6. PLATO STUDY
• NEJM 2009
• • Purpose – compare clopidogrel vs. ticagrelor
for prevention of
CV events in ACS
• • Multi-centered ,
• Enrolment time-oct,2006 to july 2008,
• Follow up upto feb,2009
• 862 centers in 43 Countries on 6 continent

7. PLATO – a global trial
Argentina
Australia
Austria
Belgium
Brazil
Bulgaria
Finland
France
Georgia
Germany
Greece
Malaysia
Mexico
The
Netherlands
Norway
Philippines
Poland
Portugal
Romania
Russia
Singapore
Slovakia
Spain
Sweden
Switzerland
South Africa
South Korea
Taiwan
Thailand
Turkey
Ukraine
United
Kingdom
United
States
Canada
China
Czech
Republic
Denmark
Hong Kong
Hungary
India
Indonesia
Israel
Italy

8. LBBB = left bundle branch block; ECG = elctrocardiogram; CABG = coronary artery bypass graft;
CAD = coronary artery disease
INCLUSION CRITERIA
• Hospitalisation for STEMI or NSTEMI ACS, with onset during the
previous 24 hours
• With STEMI, the following two inclusion criteria were required
– Persistent STEMI or new LBBB
– Primary PCI planned
• With NSTEMI ACS, at least two of the following three were required
– ST-segment 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%)
• Diabetes mellitus
• Peripheral artery disease
• Chronic renal dysfunction (creatinine clearance <60 mL/min)

9. EXCLUSION CRITERIA
• –Any contraindication to Clopidogrel
• –Previous fibrinolytic therapy within 24hr before
randomization
• –Oral anticoagulant use
• –Increased Risk of Bradycardia (not defined)
• –Concomitant therapy w/ a strong cytochrome
P-450 3A inhibitor or inducer (not defined)

10. Baseline and index event characteristics
Characteristic
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
Median age, years 62.0 62.0
Women, % 28.4 28.3
CV risk factors, %
Habitual smoker
Hypertension
Dyslipidaemia
Diabetes mellitus
36.0
65.8
46.6
24.9
35.7
65.1
46.7
25.1
History, %
Myocardial Infarction
Percutaneous coronary intervention
Coronary-artery bypass grafting
20.4
13.6
5.7
20.7
13.1
6.2
ECG at entry, %
Persistent ST-segment elevation
ST-segment depression
37.5
50.7
37.8
51.2
Troponin-I positive,* % 85.3 86.0

11. Study medication
Medication
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
Start of randomised treatment
Time after start of chest pain, h, median 11.3 11.3
Randomised treatment compliance, %
Premature discontinuation of study drug 23.4 21.5
Clopidogrel start-up, %
Clopidogrel in hospital before randomisation 46.0 46.1
Invasive procedures at index hospitalisation, %
Planned invasive treatment
Coronary angiography
PCI during index hospitalisation
Cardiac surgery
72.1
81.4
60.9
4.3
71.9
81.5
61.1
4.7

12. Therapeutic End Points
– Primary End Point was the time to first
occurrence of a composite of death from vascular
causes or no death w/ MI or stroke
– Death from vascular causes = death from any
CV cause or CVA or death w/o another known
cause
– Secondary End Point was the primary endpoint
alone in a subgroup undergoing invasiv
management

13. Additional Therapeutic End Points
• • Composite of death from any cause or no death w/
MI or stroke
• • Composite of death from vascular causes or no
death w/ MI, CVA, or arterial thrombotic events
(recurrent ischemia, TIA, etc)
• • MI alone
• • Death from CV causes alone
• • Stroke alone
• • Death from any cause alone

14. Safety End Points
• BLEEDING
• Major Life-threatening Bleeding:-
• fatal bleeding, ICH, or intrapericardial bleed w/ tamponade
• Hypovolemic shock or severe Hypotension due to bleeding that
required pressors or surgery
• • Decline in Hgb of ≥ 5g/dL
• • Need for transfusion of ≥ 4 units PRBC
• Major Bleeding:-
• • Any bleeding plus leading to significant disability (i.e.intraocular
bleeding w/ permanent vision loss, requiring at least 2 units
transfusion or Hgb drop > 3g/dL
• Minor Bleeding:-
• • Any bleeding requiring medical intervention not meeting the
• above criteria

15. Additional Safety End Points
• Dyspnea
• Bradyarrhythmia
• Any other clinical adverse event
• Results of laboratory safety tests

16. RESULT
1° Endpoint (composite of death from
vascular causes or no death w/ MI or
CVA) occurred in 9.8% vs. 11.7% at 12
mo (HR 0.84, p <0.001)

17. K-M estimate of time to first primary efficacy
event (composite of CV death, MI or stroke)
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Days after randomisation
6,743
6,743
5,096
5,161
4,047
4,147
0 60 120 180 240 300 360
12
11
10
9
8
7
6
5
4
3
2
1
0
13
Cumulativeincidence(%)
9.8
11.7
8,219
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

18. 8,688
8,763
0 10 20 30
8
6
4
2
0
Cumulativeincidence(%)
Clopidogrel
Ticagrelor
4.77
5.43
HR 0.88 (95% CI 0.77–1.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
Days after randomisation
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,673
8,286
8,397
6,379
6,480
Days after randomisation*
HR 0.80 (95% CI 0.70–0.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
Cumulativeincidence(%)
Primary efficacy endpoint over time
(composite of CV death, MI or stroke)
*Excludes patients with any primary event during the first 30 days

19. Testing major efficacy endpoints
All patients*
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
HR for
(95% CI) p value†
Primary objective, n (%)
CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001
Secondary objectives, n (%)
Total death + MI + stroke
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Myocardial infarction
CV death
Stroke
901 (10.2)
1,290 (14.6)
504 (5.8)
353 (4.0)
125 (1.5)
1,065 (12.3)
1,456 (16.7)
593 (6.9)
442 (5.1)
106 (1.3)
0.84 (0.77–0.92)
0.88 (0.81–0.95)
0.84 (0.75–0.95)
0.79 (0.69–0.91)
1.17 (0.91–1.52)
<0.001
<0.001
0.005
0.001
0.22
Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001
The percentages are K-M estimates of the rate of the endpoint at 12 months.

20. No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,560
8,678
8,405
8,520
8,177
Days after randomisation
6,703
6,796
5,136
5,210
4,109
4,191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7
Cumulativeincidence(%)
Clopidogrel
Ticagrelor
5.8
6.9
8,279
HR 0.84 (95% CI 0.75–0.95), p=0.005
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Myocardial infarction Cardiovascular death
Cumulativeincidence(%)
Secondary efficacy endpoints over time

21. Stent thrombosis
Ticagrelor
(n=5,640)
Clopidogrel
(n=5,649)
HR
(95% CI) p value
Stent thrombosis, n (%)
Definite
Probable or definite
Possible, probable, definite
71 (1.3)
118 (2.1)
155 (2.8)
106 (1.9)
158 (2.8)
202 (3.6)
0.67 (0.50–0.91)
0.75 (0.59–0.95)
0.77 (0.62–0.95)
0.009
0.02
0.01
(evaluated in patients with any stent during the study)
*Time-at-risk is calculated from first stent insertion in the study or date of randomisation

22. Time to major bleeding – primary safety event
No. at risk
Clopidogrel
Ticagrelor
9,186
9,235
7,305
7,246
6,930
6,826
6,670
Days from first IP dose
5,209
5,129
3,841
3,783
3,479
3,433
0 60 120 180 240 300 360
10
5
0
15
Clopidogrel
Ticagrelor
11.20
11.58
6,545
HR 1.04 (95% CI 0.95–1.13), p=0.434
K-Mestimatedrate(%peryear)

23. Total major bleeding
NS
NS
NS
NS
NS
0
K-Mestimatedrate(%peryear)
PLATO major
bleeding
1
2
3
4
5
6
7
8
9
10
12
11
13
TIMI major
bleeding
Red cell
transfusion*
PLATO life-
threatening/
fatal bleeding
Fatal bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use
of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15;
*Proportion of patients (%); NS = not significant
11.6
11.2
7.9
7.7
8.9 8.9
5.8 5.8
0.3 0.3
Ticagrelor
Clopidogre
l

24. Non-CABG and CABG-related major bleeding
p=0.026
p=0.025
NS
NS
9K-Mestimatedrate(%peryear)
Non-CABG
PLATO major
bleeding
8
7
6
5
4
3
2
1
0
Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
Ticagrelor
Clopidogrel

25. Holter monitoring & Bradycardia related events
Holter monitoring at first week
Ticagrelor
(n=1,451)
Clopidogrel
(n=1,415) p value
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds, %
5.8
2.0
3.6
1.2
0.01
0.10
Holter monitoring at 30 days
Ticagrelor
(n= 985)
Clopidogrel
(n=1,006) p value
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds, %
2.1
0.8
1.7
0.6
0.52
0.60
Bradycardia-related event, %
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) p value
Pacemaker Insertion
Syncope
Bradycardia
Heart block
0.9
1.1
4.4
0.7
0.9
0.8
4.0
0.7
0.87
0.08
0.21
1.00

26. Other findings
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) p value*
Dyspnoea, %
Any
With discontinuation of study treatment
13.8
0.9
7.8
0.1
<0.001
<0.001
Neoplasms arising during treatment, %
Any
Malignant
Benign
1.4
1.2
0.2
1.7
1.3
0.4
0.17
0.69
0.02
*p values were calculated using Fischer’s exact test

27. Other findings – laboratory parameters
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) p value*
% increase in creatinine from baseline
At 1 month
At 12 months
Follow-up visit
10  22
11  22
10  22
8  21
9  22
10  22
<0.001
<0.001
0.59
% increase in uric acid from baseline
At 1 month
At 12 months
Follow-up visit
14  46
15  52
7  43
7  44
7  31
8  48
<0.001
<0.001
0.56
Values are mean %  SD; *p values were calculated using Fisher’s exact test

28. DISCUSSION
• Advantages
• Lower mortality
• Comparable major bleeding risk
• Faster and more intense platelet inhibition
• Reversible
• Disadvantages
• Expense, familiarity
• BID dosing vs. daily for Plavix(clopidegrel)
• Increased non-major bleeding

29. Conclusions
• Reversible, more intense P2Y12 receptor inhibition for one year
with ticagrelor in comparison with clopidogrel in a broad
population with ST- and non-ST-elevation ACS provides
– Reduction in myocardial infarction and stent thrombosis
– Reduction in cardiovascular and total mortality
– No change in the overall risk of major bleeding
– -Increse incidence SOB.
Ticagrelor is a more effective alternative than clopidogrel
for the continuous prevention of ischaemic events, stent
thrombosis and death in the acute and long-term treatment
of patients with ACS

30. Thanks 