cannon plato invasive
TRANSCRIPT
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Ticagrelor compared with clopidogrel
in patients with acute coronarysyndromes 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
Invasive
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InvasivePLATO 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
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Invasive
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
OH
OH
O
OH
N
S
NH
N
N
NN
F
F
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InvasivePLATO study design
612 months treatment
PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator
NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624)
Clopidogrel-treated or -naive; randomized
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InvasiveBaseline and index event characteristics
Characteristic
Ticagrelor
(n=6,732)Clopidogrel(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
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 elevationST-segment depression
T-wave inversion
48.452.8
28.7
49.354.0
29.4
Troponin-I positive (central lab, first) % 82.3 84.0
Median time from chest pain to rand., h 8.8 9.0
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InvasiveProcedures and timing*
Procedure
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
Invasive procedures at index hospitalization, % (n)
Coronary angiography
Median (IQR), hours
PCI during index hospitalization % (n)
Median (IQR), hours
UA/NSTEMI PCI % (n)
Median (IQR), hours
STEMI - Primary PCI % (n)
Median (IQR), hours
Coronary by-pass surgery pre-discharge % (n)
Median (IQR), hours
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
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InvasiveCo-medication
Medication
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
Anti-thrombotic treatment in hospital, %
Aspirin
Unfractionated heparin
Low molecular weight heparinFondaparinux
Bivalirudin
GP IIb/IIIa inhibitor
97.7
35.1
41.11.6
1.2
19.7
97.9
36.0
40.91.8
1.3
20.3
Other medication in hospital or at discharge, %
Beta-blockadeACE /ARB
Cholesterol lowering (statin)
Proton pump inhibitor
85.587.0
95.4
54.4
86.186.8
95.5
53.7
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Invasive
Treatment
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
Clopidogrel %
Prior to hospitalization 7.3 6.7
Open-label Clopidogrel pre-Randomization, %
None or missing information
75 mg300 mg
600 mg
55.3
8.3
19.3
17.1
54.7
8.119.8
16.6
Study drug Clopidogrel (or placebo for Tic) in first 24 h
None
75 mg
300 mg600 mg
Total Clopidogrel (OL+IP) pre-Randomization to 24 h
300 mg
600 mg
Premature discontinuation of study drug, %
1.5
44.2
46.48.0
69.1
30.9
23.1
1.4
44.2
46.58.0
69.9
30.1
21.8
Clopidogrel / Ticagrelor treatment
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InvasivePrimary endpoint: CV death, MI or stroke
0
0
5
10
15
60 120 180 240 300 360
Days after randomization
K-Me
stimated
rate(%p
eryear)
HR: 0.84 (95% CI = 0.750.94), p=0.0025
9.02
10.65Clopidogrel
Ticagrelor
No. at risk
Clopidogrel
Ticagrelor
6,676
6,732
6,129
6,236
6,034
6,134
5,881 4,815
4,889
3,680
3,735
2,965
3,0485,972
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
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Invasive
Hierarchical testing of major efficacy
endpoints
Endpoint* 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 (0.750.94) 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
0.84 (0.750.94)
0.85 (0.770.93)
0.80 (0.690.92)
0.82 (0.680.98)
1.08 (0.781.50)
0.001
0.0005
0.002
0.025
0.646
Total (all-cause) death 3.9 5.1 0.81 (0.680.95) 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
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Invasive
No. at risk
Clopidogrel
Ticagrelor
6,676
6,732
6,157
6,268
6,062
6,173
5,917
Days after randomization
4,849
4,924
3,706
3,766
2,987
3,078
0 60 120 180 240 300 360
8
6
4
2
0
Cumulativeincidence(%)
Clopidogrel
Ticagrelor
5.3
6.6
6,010
0 60 120 180 240 300 360
8
4
2
0
Clopidogrel
Ticagrelor3.4
4.3
6
6,676
6,732
6,376
6,439
6,332
6,375
6,209
Days after randomization
5,114
5,141
3,917
3,591
3,164
3,2336,241
Myocardial infarction Cardiovascular death
Cumulativein
cidence(%)
HR 0.80 (95% CI = 0.690.92), p=0.002 HR 0.82 (95% CI = 0.680.98), p=0.025
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InvasiveAll-cause mortality
6
4
2
00 60 120 180 240 300 360
Clopidogrel
Ticagrelor
Days after randomization
K-Me
stimatedra
te(%p
eryear)
5.08
3.94
HR 0.81 (95% CI = 0.680.95), p=0.01
No. at risk
Clopidogrel
Ticagrelor
6,676
6,732
6,376
6,439
6,331
6,375
6,209 5,114
5,141
3,917
3,951
3,164
3,2336,241
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InvasiveStent 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 (0.450.85)
0.72 (0.560.93)
0.72 (0.580.90)
0.003
0.01
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
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InvasivePrimary efficacy endpoint by clopidogrel
loading dose
Ticagrelor better Clopidogrel better
0.5 1.0 2.00.2
Ti. Cl.
Total
Patients
KM % atMonth 12
HR (95% CI)
HazardRatio
(95% CI)
Clopidogrel loading dose
(Pre-rand. + Study drug)
Characteristic
4091 8.0 9.5 0.83 (0.67, 1.03)600 mg
9.5 11.2 0.85 (0.74, 0.96)300 mg
p value
(Interaction)
0.917
9314
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InvasivePrimary safety event: Major bleeding*
No. at risk
Clopidogrel
Ticagrelor
6,585
6,651
5,215
5,235
4,984
4,947
4,786
Days after randomization
3,753
3,726
2,754
2,741
2,496
2,503
0 60 120 180 240 300 360
10
5
0
15
Clopidogrel
Ticagrelor
11.6
11.5
4,755
K-M
estimate
drate(%p
eryea
r)
HR 0.99 (95% CI = 0.891.10), p=0.88
* PLATO definitions
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InvasiveLife-threatening or fatal bleeding*
K-M
estimat
edrate(%p
eryea
r)
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
0 60 120 180 240 300 360
6
2
0
8
4,945
HR 1.04 (95% CI = 0.901.20), p=0.61
4
Clopidogrel
Ticagrelor
5.9
6.0
* PLATO definitions
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InvasiveTotal major 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;357:200115;
NS = not significant
NS
NS
NS
NS
NS
0
K-Me
stimatedrate(%p
eryear)
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
11.5 11.6
8.0 8.0
8.9 8.8
6.0 5.9
0.2 0.3
Ticagrelor
Clopidogrel
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Invasive
Ticagrelor
Clopidogrel
NS
NS
NS
0
K
-M
estimatedrate(%p
eryear)
PLATO major
bleeding
1
2
3
4
5
6
7
8
9
10
12
11
13
TIMI major bleeding
11.5 11.6
8.0 8.0
2.93.2
GUSTO severe
bleeding*
4.7
4.1
2.8 2.3
1.9
1.7
Non-CABG and CABG-related major bleeding
Non-CABG
CABG
*Preliminary from eCRF
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InvasiveBradycardia-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
0.5
1.0
5.1
2.4
0.4
0.4
0.6
0.5
1.1
0.26
0.24
0.89
0.15
0.26
1.00
0.73
All patients
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676) p value*
Dyspnea, %
Any dyspnea event
Requiring discontinuation of study-
treatment
15.4
0.9
10.4
0.3
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InvasiveTherapeutic considerations
Based on 1,000 patients admitted to hospital for ACS and planned
for invasive strategy, using ticagrelor instead of clopidogrel for 12months 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 forone year will prevent one event of CV death, MI or stroke
Treating 88 will save one life (in one year)
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InvasiveConclusions
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