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
PLATO background
Invasive

• 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
Ticagrelor (AZD 6140): an oral reversible
P2Y12 antagonist Invasive

HO
N
N
N
HO H
N F Ticagrelor is a cyclo-pentyl-
O N triazolo-pyrimidine (CPTP)
N
F
S
OH

• 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
PLATO study design
Invasive

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)
Ticagrelor (n=6,732)
If pre-treated, no additional loading dose;
180 mg loading dose, then
if naive, standard 300 mg loading dose,
90 mg bid maintenance;
then 75 mg qd maintenance;
(additional 90 mg pre-PCI)
(additional 300 mg allowed 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

Baseline and index event characteristics
Invasive

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

Ticagrelor Clopidogrel
Procedure (n=6,732) (n=6,676)

Invasive procedures at index hospitalization, % (n)

Coronary angiography 96.8 (6514) 96.9 (6471)
Median (IQR), hours 0.62 (0.10, 3.70) 0.62 (0.12, 3.65)

PCI during index hospitalization % (n) 76.7 (5166) 77.1 (5148)

Median (IQR), hours 0.77 (0.30, 2.75) 0.78 (0.32, 2.65)

UA/NSTEMI – PCI % (n) 63.8 (1882) 64.8 (1854)

Median (IQR), hours 2.63 (0.78, 21.10) 2.60 (0.87, 21.30)

STEMI - Primary PCI % (n) 83.2 (3138) 82.7 (3149)

Median (IQR), hours 0.47 (0.23, 0.95) 0.48 (0.23, 0.95)

Coronary by-pass surgery pre-discharge % (n) 5.5 (372) 6.1 (410)

Median (IQR), hours 117 (47, 216) 121 (48, 218)

* Time between randomization and first procedure

Co-medication
Invasive

Ticagrelor Clopidogrel
Medication (n=6,732) (n=6,676)

Anti-thrombotic treatment in hospital, %

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

Ticagrelor Clopidogrel
Treatment (n=6,732) (n=6,676)
Clopidogrel %
Prior to hospitalization 7.3 6.7

Open-label Clopidogrel pre-Randomization, %

None or missing information 55.3 54.7
75 mg 8.3 8.1
300 mg 19.3 19.8
600 mg 17.1 16.6
Study drug Clopidogrel (or placebo for Tic) in first 24 h
None 1.5 1.4
75 mg 44.2 44.2
300 mg 46.4 46.5
600 mg 8.0 8.0
Total Clopidogrel (OL+IP) pre-Randomization to 24 h
300 mg 69.1 69.9
600 mg 30.9 30.1
Premature discontinuation of study drug, % 23.1 21.8
 Primary endpoint: CV death, MI or stroke Invasive

15
K-M estimated rate (% per year)

Clopidogrel
10.65
10
9.02
Ticagrelor

HR: 0.84 (95% CI = 0.75–0.94), p=0.0025

0
0 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

 Hierarchical testing of major efficacy
endpoints Invasive

HR for
Ticagrelor Clopidogrel ticagrelor
Endpoint* (n=6,732) (n=6,676) (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 9.4 11.2 0.84 (0.75–0.94) 0.001

CV death + MI + stroke + 13.2 15.3 0.85 (0.77–0.93) 0.0005

ischaemia + TIA + arterial
thrombotic events
MI 5.3 6.6 0.80 (0.69–0.92) 0.002
CV death 3.4 4.3 0.82 (0.68–0.98) 0.025
Stroke 1.2 1.1 1.08 (0.78–1.50) 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
 Invasive

Myocardial infarction Cardiovascular death

8 8
Cumulative incidence (%)

Cumulative incidence (%)

Clopidogrel 6.6
6 6

5.3
Clopidogrel
Ticagrelor 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

0 0
0 60 120 180 240 300 360 0 60 120 180 240 300 360
No. at risk Days after randomization Days after randomization

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
 All-cause mortality Invasive

6
K-M estimated rate (% per year)

Clopidogrel
5.08
4
3.94
Ticagrelor

HR 0.81 (95% CI = 0.68–0.95), p=0.01

0
0 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

 Stent thrombosis Invasive

Ticagrelor Clopidogrel HR for ticagrelor

(n=6,732) (n=6,676) (95% CI) p value*

Stent thrombosis, %

Definite 1.0 1.6 0.62 (0.45–0.85) 0.003

Probable or definite 1.7 2.3 0.72 (0.56–0.93) 0.01

Possible, probable, or definite 2.2 3.1 0.72 (0.58–0.90) 0.003

¶
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
 Primary efficacy endpoint by clopidogrel
Invasive
loading dose

Hazard KM % at
Ratio Total Month 12 p value
Characteristic (95% CI) Patients Ti. Cl. HR (95% CI) (Interaction)

Clopidogrel loading dose 0.917

(Pre-rand. + Study drug)
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

Primary safety event: Major bleeding* Invasive

15

K-M estimated rate (% per year)

Clopidogrel
11.6
10 Ticagrelor 11.5

HR 0.99 (95% CI = 0.89–1.10), p=0.88

0
0 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
Life-threatening or fatal bleeding*
Invasive

8
K-M estimated rate (% per year)
Ticagrelor 6.0
6
5.9
Clopidogrel

HR 1.04 (95% CI = 0.90–1.20), p=0.61

0
0 60 120 180 240 300 360
Days from first IP dose
No. at risk
Ticagrelor 6,651 5,387 5,113 4,945 3,890 2,866 2,634
Clopidogrel 6,585 5,400 5,180 5,009 3,934 2,898 2,635

*
PLATO definitions
Total major bleeding
Invasive
13 NS
Ticagrelor
12 11.5 11.6 Clopidogrel
11
NS
10
K-M estimated rate (% per year)

NS 8.9 8.8
9
8.0 8.0
8
7 NS
6.0 5.9
6
5
4
3
2
NS
1 0.2 0.3
0
PLATO major TIMI major Red cell PLATO life- Fatal bleeding
bleeding bleeding transfusion threatening/
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
Non-CABG and CABG-related major bleeding
Invasive
13 NS
Ticagrelor
11.5 11.6
12 Clopidogrel
11 4.7
K-M estimated rate (% per year)

Non-CABG
10
9 4.1 NS
8.0 8.0
8
7
2.8 2.3
6
5
NS
CABG

4 3.2
2.9
3
1.7
2
1.9
1
0
PLATO major TIMI major bleeding GUSTO severe
bleeding bleeding*

*Preliminary – from eCRF

Bradycardia-related events and other findings Invasive

Ticagrelor Clopidogrel
All patients (n=6,732) (n=6,676) p value*

Bradycardia-related event, %
Any bradycardia event 5.5 5.1 0.26
Symptomatic event 2.1 2.4 0.24
Sick sinus syndrome or sinus pause 0.4 0.4 0.89
AV Block II-III 0.5 0.4 0.15
Temporary pacemaker used 0.8 0.6 0.26
Permanent pacemaker implanted 0.5 0.5 1.00
Considered serious adverse event 1.0 1.1 0.73
Ticagrelor Clopidogrel
All patients (n=6,732) (n=6,676) p value*

Dyspnea, %
Any dyspnea event 15.4 10.4 <0.0001
Requiring discontinuation of study- 0.9 0.3 < 0.0001
treatment

*p values calculated using Fisher’s Exact test

Therapeutic considerations
Invasive

• 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)

 Conclusions
Invasive

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