I NVOLVING CHILDREN & YOUNG PEOPLE IN COMMISSIONING (T OOLKIT ) R ECORDED O UTCOMES T RAINING.
Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet...
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Transcript of Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet...
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
Invasive
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
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
NN
NN
F
F
InvasivePLATO study design
6–12 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 <24 hours of index event
At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy
Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding
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)
InvasiveBaseline and index event characteristics
CharacteristicTicagrelor(n=6,732)
Clopidogrel(n=6,676)
Median age, years 61.0 61.0 Age ≥75 years, % 12.5 13.9Women, % 25.2 25.3Diabetes mellitus 22.8 23.7
History, % Myocardial infarction Percutaneous coronary intervention Coronary-artery bypass graft
17.114.15.3
17.013.35.7
ECG and Troponin at entry, % Persistent ST-segment elevation ST-segment depression T-wave inversion
48.452.8 28.7
49.354.029.4
Troponin-I positive (central lab, first) % 82.3 84.0
Median time from chest pain to rand., h 8.8 9.0
InvasiveProcedures and timing*
ProcedureTicagrelor(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
InvasiveCo-medication
MedicationTicagrelor(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
Invasive
TreatmentTicagrelor(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 mg 300 mg 600 mg
55.38.3
19.317.1
54.78.119.816.6
Study drug Clopidogrel (or placebo for Tic) in first 24 h None 75 mg 300 mg 600 mg
Total Clopidogrel (OL+IP) pre-Randomization to 24 h 300 mg 600 mg
Premature discontinuation of study drug, %
1.544.246.48.0
69.130.9
23.1
1.444.246.58.0
69.930.1
21.8
Clopidogrel / Ticagrelor treatment
InvasivePrimary endpoint: CV death, MI or stroke
0
0
5
10
15
60 120 180 240 300 360
Days after randomization
K-M
est
ima
ted
rat
e (%
per
ye
ar)
HR: 0.84 (95% CI = 0.75–0.94), 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
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 (0.75–0.94) 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
0.84 (0.75–0.94)
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
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
Cu
mu
lati
ve i
nci
de
nce
(%
)
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
Cu
mu
lati
ve i
nci
de
nce
(%
)
HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025
InvasiveAll-cause mortality
6
4
2
0
0 60 120 180 240 300 360
Clopidogrel
Ticagrelor
Days after randomization
K-M
est
ima
ted
rat
e (%
per
ye
ar)
5.08
3.94
HR 0.81 (95% CI = 0.68–0.95), 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
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 (0.45–0.85)
0.72 (0.56–0.93)
0.72 (0.58–0.90)
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
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)
Hazard Ratio
(95% CI)
Clopidogrel loading dose (Pre-rand. + Study drug)
Characteristic
4091 8.0 9.5 0.83 (0.67, 1.03)600 mg9.5 11.2 0.85 (0.74, 0.96)300 mg
p value(Interaction)
0.917
9314
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
est
imat
ed r
ate
(% p
er y
ear)
HR 0.99 (95% CI = 0.89–1.10), p=0.88
* PLATO definitions
InvasiveLife-threatening or fatal bleeding*
K-M
est
imat
ed r
ate
(% p
er y
ear)
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 = 0.90–1.20), p=0.61
4
Clopidogrel
Ticagrelor
5.96.0
* PLATO definitions
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;357:2001–15; NS = not significant
NS
NS
NS
NS
NS
0
K-M
est
ima
ted
rat
e (%
per
ye
ar)
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
TicagrelorClopidogrel
Invasive
TicagrelorClopidogrel
NS
NS
NS
0
K-M
est
imat
ed r
ate
(% p
er y
ear)
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
No
n-C
AB
GC
AB
G
*Preliminary – from eCRF
InvasiveBradycardia-related events and other findings
All patientsTicagrelor(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 patientsTicagrelor(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
<0.0001
< 0.0001
*p values calculated using Fisher’s Exact test
InvasiveTherapeutic 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)
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