1. Invasive
Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATelet Inhibition and patient Outcomes trial
Outcomes in patients with a Planned Invasive Strategy
The PLATO trial was funded by AstraZeneca
Dr. Cannon discloses research grants/support from the following companies: Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering Plough Partnership, Novartis and Takeda; and equity in Automedics Medical Systems

2. Efficacy of clopidogrel is hampered by
PLATO background
In STEMI and UA/NSTEMI, current guidelines recommend 12 months of aspirin and clopidogrel
Efficacy of clopidogrel is hampered by
slow and variable transformation to the active metabolite (e.g. 2C19)
modest and variable platelet inhibition
 risk stent thrombosis and MI in poor responders
Irreversible effect – and increased risk of bleeding if urgent CABG is required
PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation; STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction

3. Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
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 circulating platelets within ~48 hours

4. PLATO study design
NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624)
Clopidogrel-treated or -naive; randomized <24 hours of index event
At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy
Clopidogrel (n=6,676)
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 (n=6,732)
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12 months treatment
Primary endpoint: CV death + MI + Stroke
Primary safety endpoint: Total major bleeding
PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator

5. Baseline and index event characteristics
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
Median age, years
61.0
Age ≥75 years, %
12.5
13.9
Women, %
25.2
25.3
Diabetes mellitus
22.8
23.7
History, %
Myocardial infarction
Percutaneous coronary intervention
Coronary-artery bypass graft
17.1
14.1
5.3
17.0
13.3
5.7
ECG and Troponin at entry, %
Persistent ST-segment elevation
ST-segment depression
T-wave inversion
48.4
52.8
28.7
49.3
54.0
29.4
Troponin-I positive (central lab, first) %
82.3
84.0
Median time from chest pain to rand., h
8.8
9.0

6. Procedures and timing*
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
Invasive procedures at index hospitalization, % (n) Coronary angiography
Median (IQR), hours
PCI during index hospitalization % (n)
UA/NSTEMI – PCI % (n)
STEMI - Primary PCI % (n)
Coronary by-pass surgery pre-discharge % (n)
96.8 (6514)
0.62 (0.10, 3.70)
76.7 (5166)
0.77 (0.30, 2.75)
63.8 (1882)
2.63 (0.78, 21.10)
83.2 (3138) 0.47 (0.23, 0.95)
5.5 (372)
117 (47, 216)
96.9 (6471)
0.62 (0.12, 3.65)
77.1 (5148)
0.78 (0.32, 2.65)
64.8 (1854)
2.60 (0.87, 21.30)
82.7 (3149)
0.48 (0.23, 0.95)
6.1 (410)
121 (48, 218)
* Time between randomization and first procedure

7. Co-medication Medication Ticagrelor (n=6,732) Clopidogrel (n=6,676)
Anti-thrombotic treatment in hospital, %
Aspirin
Unfractionated heparin
Low molecular weight heparin
Fondaparinux
Bivalirudin
GP IIb/IIIa inhibitor
97.7
35.1
41.1
1.6
1.2
19.7
97.9
36.0
40.9
1.8
1.3
20.3
Other medication in hospital or at discharge, %
Beta-blockade
ACE /ARB
Cholesterol lowering (statin)
Proton pump inhibitor
85.5
87.0
95.4
54.4
86.1
86.8
95.5
53.7

8. Clopidogrel / Ticagrelor treatment
Prior to hospitalization
7.3
6.7
Open-label Clopidogrel pre-Randomization, %
None or missing information
75 mg
300 mg
600 mg
55.3
8.3
19.3
17.1
54.7
8.1
19.8
16.6
Study drug Clopidogrel (or placebo for Tic) in first 24 h
None
Total Clopidogrel (OL+IP) pre-Randomization to 24 h
Premature discontinuation of study drug, %
1.5
44.2
46.4
8.0
69.1
30.9
23.1
1.4
46.5
69.9
30.1
21.8

9. Primary endpoint: CV death, MI or stroke15
Clopidogrel
10.65 10
9.02
K-M estimated rate (% per year)
Ticagrelor 5
HR: 0.84 (95% CI = 0.75–0.94), p=0.0025 60
120
180
240
300
360
Days after randomization
No. at risk
Ticagrelor
6,732
6,236
6,134
5,972
4,889
3,735
3,048
Clopidogrel
6,676
6,129
6,034
5,881
4,815
3,680
2,965
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

10. Hierarchical testing of major efficacy endpoints
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
HR for ticagrelor
(95% CI)
p value†
Primary objective, %
CV death + MI + stroke
9.0
10.7
0.84 (0.75–0.94)
0.0025
Secondary objectives, %
Total death + MI + stroke
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events MI
CV death
Stroke
9.4
13.2
5.3
3.4
1.2
11.2
15.3
6.6
4.3
1.1
0.85 (0.77–0.93)
0.80 (0.69–0.92)
0.82 (0.68–0.98)
1.08 (0.78–1.50)
0.001
0.0005
0.002
0.025
0.646
Total (all-cause) death
3.9
5.1
0.81 (0.68–0.95)
0.010
*The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. †By univariate Cox model

11. Myocardial infarction Cardiovascular death8 8
Clopidogrel
6.6 6 6
5.3
Cumulative incidence (%)
Clopidogrel
Ticagrelor
Cumulative incidence (%)
4.3 4 4
3.4
Ticagrelor 2 2
HR 0.80 (95% CI = 0.69–0.92), p=0.002
HR 0.82 (95% CI = 0.68–0.98), p=0.025 60
120
180
240
300
360 60
120
180
240
300
360
Days after randomization
Days after randomization
No. at risk
Ticagrelor
6,732
6,268
6,173
6,010
4,924
3,766
3,078
6,732
6,439
6,375
6,241
5,141
3,591
3,233
Clopidogrel
6,676
6,157
6,062
5,917
4,849
3,706
2,987
6,676
6,376
6,332
6,209
5,114
3,917
3,164

12. Days after randomization
All-cause mortality 6
Clopidogrel
5.08 4
3.94
Ticagrelor
K-M estimated rate (% per year) 2
HR 0.81 (95% CI = 0.68–0.95), p=0.01 60
120
180
240
300
360
No. at risk
Days after randomization
Ticagrelor
6,732
6,439
6,375
6,241
5,141
3,951
3,233
Clopidogrel
6,676
6,376
6,331
6,209
5,114
3,917
3,164

13. Stent thrombosis Ticagrelor (n=6,732) Clopidogrel (n=6,676)
HR for ticagrelor
(95% CI)
p value*
Stent thrombosis, %
Definite
Probable or definite
Possible, probable, or definite
1.0
1.7
2.2
1.6
2.3
3.1
0.62 (0.45–0.85)
0.72 (0.56–0.93)
0.72 (0.58–0.90)
0.003
0.01
¶ Evaluated in patients with any stent during the study
Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization * By univariate Cox model

14. Primary efficacy endpoint by clopidogrel loading dose
KM % at Month 12
Hazard Ratio (95% CI)
Total Patients
p value (Interaction)
Characteristic
Ti.
Cl.
HR (95% CI)
Clopidogrel loading dose (Pre-rand. + Study drug)
0.917
300 mg
9314
9.5
11.2
0.85 (0.74, 0.96)
600 mg
4091
8.0
9.5
0.83 (0.67, 1.03)
0.2
0.5
1.0
2.0
Ticagrelor better
Clopidogrel better

15. Primary safety event: Major bleeding*15
Clopidogrel
11.6
Ticagrelor
11.5 10
K-M estimated rate (% per year) 5
HR 0.99 (95% CI = 0.89–1.10), p=0.88 60
120
180
240
300
360
Days after randomization
No. at risk
Ticagrelor
6,651
5,235
4,947
4,755
3,726
2,741
2,503
Clopidogrel
6,585
5,215
4,984
4,786
3,753
2,754
2,496
* PLATO definitions

16. Life-threatening or fatal bleeding*
No. at risk
Clopidogrel
Ticagrelor
6,585
6,651
5,400
5,387
5,180
5,113
5,009
Days from first IP dose
3,934
3,890
2,898
2,866
2,635
2,634 60
120
180
240
300
360 6 2 8
4,945
HR 1.04 (95% CI = 0.90–1.20), p=0.61 4
5.9
6.0
K-M estimated rate (% per year)
* PLATO definitions

17. K-M estimated rate (% per year) PLATO life-threatening/ fatal bleeding
Total major bleeding 13 NS
Ticagrelor
Clopidogrel 12
11.5
11.6 11 NS 10 NS
8.9 9
8.8
8.0
8.0 8 7 NS
K-M estimated rate (% per year)
6.0 6
5.9 5 4 3 2 NS 1
0.2
0.3
PLATO major bleeding
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; NS = not significant

18. Non-CABG and CABG-related major bleeding13 NS
Ticagrelor
Clopidogrel 12
11.5
11.6 11
4.7 10 NS 9
4.1
Non-CABG
8.0
8.0 8 7
K-M estimated rate (% per year)
2.3
2.8 6 5 NS 4
CABG
3.2
2.9 3
1.7 2
1.9 1
PLATO major bleeding
TIMI major bleeding
GUSTO severe bleeding*
*Preliminary – from eCRF

19. Bradycardia-related events and other findings
All patients
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
p value*
Bradycardia-related event, %
Any bradycardia event
Symptomatic event
Sick sinus syndrome or sinus pause
AV Block II-III
Temporary pacemaker used
Permanent pacemaker implanted
Considered serious adverse event
5.5
2.1
0.4
0.5
0.8
1.0
5.1
2.4
0.6
1.1
0.26
0.24
0.89
0.15
1.00
0.73
Dyspnea, %
Any dyspnea event
Requiring discontinuation of study-
treatment
15.4
0.9
10.4
0.3
<0.0001
<
*p values calculated using Fisher’s Exact test

20. Therapeutic considerations
Based on 1,000 patients admitted to hospital for ACS and planned for invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in
11 fewer deaths
13 fewer myocardial infarctions
6 fewer cases with stent thrombosis
No increase in major bleeding or need for transfusion
6 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnoea
Treating 59 patients with ticagrelor instead of with clopidogrel for one year will prevent one event of CV death, MI or stroke
Treating 88 will save one life (in one year)

21. for the continuous prevention of ischemic events,
Conclusions
Ticagrelor, the reversible, more intense P2Y12 antagonist, is a more effective alternative to clopidogrel for one year in ACS patients managed with an invasive strategy,
for the continuous prevention of ischemic events,
stent thrombosis and death without an increase in major bleeding