Ticagrelor versus clopidogrel in patients
with acute coronary syndromes undergoing
coronary artery bypass surgery: results from
the PLATO trial
The PLATO trial was funded by AstraZeneca
Dr. Held discloses research grants/support from the following companies: AstraZeneca, GlaxoSmithKline,
Schering-Plough, Sanofi-Aventis, Pfizer, Bristol-Myers Squibb
PLATO background
Study drug ≤7 days
before CABG
• In NSTEMI and STEMI ACS, current guidelines recommend
12 months’ treatment with aspirin and clopidogrel
• Clopidogrel has been studied extensively and used to treat millions
of ACS patients successfully, but its efficacy is hampered by
–
–
–
–
slow and variable transformation to the active metabolite
modest and variable platelet inhibition
risk of stent thrombosis and MI in poor responders
irreversible effect – and increased risk of bleeding if urgent CABG
is required
• In patients with an urgent need for CABG, clopidogrel is
recommended to be withdrawn 5 days prior to surgery
• Clinical reality often require surgery earlier and a rapid offset of the
antiplatelet therapy is preferred
PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation; STEMI = ST segment elevation;
ACS = acute coronary syndromes; MI = myocardial infarction; CABG = coronary artery bypass graft
Ticagrelor (AZD 6140): an oral reversible
P2Y12 antagonist
HO
N
N
N
H
N
HO
O
N
Study drug ≤7 days
before CABG
F
N
S
Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP)
F
OH
• Direct acting
– Not a pro-drug; 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
Study drug ≤7 days
before CABG
NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624)
Clopidogrel-treated or -naive; randomized <24 hours of index event
After randomization, 1,261 patients underwent CABG and were on
study drug treatment for ≤7 days prior to surgery
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)
6–12 months treatment
Primary endpoint: CV death + MI + Stroke
Primary safety endpoint: Total major bleeding
Recommendations for patients undergoing CABG:
Study drugs withheld prior to surgery – 5 days for clopidogrel and
24–72 hours for ticagrelor. Study drug be restarted as soon as
possible after surgery and prior to discharge
PCI = percutaneous coronary intervention
CV = cardiovascular
PLATO main endpoints*
Study drug ≤7 days
before CABG
Primary safety endpoint
Primary efficacy endpoint
13
15
12
11.7
Clopidogrel
11
K-M estimated rate (%)
9.8
9
Ticagrelor
8
7
6
5
4
3
K-M estimated rate (%)
Ticagrelor
10
10
11.58
11.20
Clopidogrel
5
2
HR 0.84 (95% CI 0.77–0.92), p=0.0003
1
0
0
0
No. at risk
HR 1.04 (95% CI 0.95–1.13), p=0.434
2
4
6
8
10
12
0
Months from randomization
2
4
6
8
10
12
Months from randomization
Ticagrelor
9,333 8,628 8,460 8,219 6,743 5,161 4,147
9,235
7,246
6,826 6,545 5,129 3,783 3,433
Clopidogrel
9,291 8,521 8,362 8,124 6,743 5,096 4,047
9,186
7,305
6,930 6,670 5,209 3,841 3,479
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
* Wallentin, L et al., New Eng J Med. 2009;361:1045–1057
Objectives
Study drug ≤7 days
before CABG
• Antiplatelet therapy currently recommended in ACS is
clopidogrel and aspirin
• Recovery of platelet function occurs after 5–7 days following
irreversible platelet inhibition by aspirin and clopidogrel
– This can increase the risk of complications in patients urgently needing
major surgery such as CABG
• However, the reversible P2Y12 inhibition provided by ticagrelor
could shorten this interval to 2–3 days
• The objective of this pre-defined PLATO analysis was to evaluate
the efficacy and safety after CABG (in patients with last intake of
study drug within 7 days of surgery)
Patient disposition
Study drug ≤7 days
before CABG
18,758 patients
enrolled in PLATO
134 patients not
randomized
18,624 patients
randomized
Non-CABG:
16,725 patients
CABG: 1,899 patients
Last intake of study
drug ≤7 days prior to
surgery: 1,261 patients
632 patients treated
with ticagrelor
629 patients treated
with clopidogrel
Baseline characteristics of patients undergoing CABG
with last intake of study drug within 7 days of surgery
Study drug ≤7 days
before CABG
Ticagrelor
(n=632)
Clopidogrel
(n=629)
Median age, years
64
64
Age >75 years, %
13.6
15.7
Caucasian
93.0
93.5
Black
1.3
1.4
Oriental
4.1
3.7
Other
1.6
1.4
Men, %
80.9
76.9
Women, %
19.1
23.1
Characteristic
Race, %
Men
Women
Men
Women
Median weight, kg
82
70
81
71
Weight <60 kg, %
2.9
13.2
3.3
15.9
Median height, m
1.72
1.62
1.73
1.60
Median body mass index, kg/m2
27.6
26.8
26.9
27.1
Median waist circumference, cm
99
98
99
97
Baseline CV risk and history
Study drug ≤7 days
before CABG
Ticagrelor
(n=632)
Clopidogrel
(n=629)
CV risk factors, %
Smoker
Hypertension
Dyslipidemia
Diabetes
32.9
68.5
56.3
30.5
29.4
67.1
52.1
32.9
CV history, %
Angina pectoris
MI
Congestive heart failure
PCI
CABG
Transient ischemic attack
Non-hemorrhagic stroke
Peripheral artery disease
Chronic renal disease
54.4
19.6
4.7
9.2
0.8
3.3
3.8
6.8
5.2
52.0
20.8
3.5
11.6
2.2
2.9
4.0
8.4
4.3
Characteristic
Evaluations and invasive procedures
Study drug ≤7 days
before CABG
Ticagrelor
(n=632)
Clopidogrel
(n=629)
17.1
17.0
Median heart rate, bpm
72
73
Median systolic blood pressure, mmHg
131
132
Median diastolic blood pressure, mmHg
80
80
Killip class >2, %
1.4
1.8
Persistent ST-segment elevation >1mm /
32.6
33.4
59.2
55.2
Coronary angiography
89.2
90.1
PCI within 24 hours of randomization
17.7
20.0
Any PCI pre-discharge
20.6
21.5
Any CABG pre-discharge
55.7
58.5
Characteristic
Evaluations
Abnormal physical findings, %
LBBB/final diagnosis of STEMI, %
TIMI STEMI risk score >2, %
Invasive procedures in hospital, %
bpm = beats per minute; LBBB = left bundle branch block; TIMI = thrombolysis in myocardial infarction
Study medication
Study drug ≤7 days
before CABG
Ticagrelor
(n=632)
Clopidogrel
(n=629)
226 (26–364)
223 (28–353)
Median delay from start of pain, h
14.4
13.5
Median delay from hospital admission, h
9.0
6.8
Medication
Median treatment duration, days (range)
Total clopidogrel (OL + IP) pre-randomization to 24 h, %
300 mg
83.4
81.2
600 mg
16.6
18.8
None
53.5
55.8
75 mg (50–150 mg)
14.9
10.5
300 mg (151–449 mg)
22.5
21.5
600 mg (≥450 mg)
9.2
12.2
Open-label clopidogrel pre-randomization, %
OL = open-label; IP = investigational product
Study medication pre- and post-CABG
Days study drug stopped before CABG, %
1 day
2 days
3 days
4 days
5 days
6 days
7 days
Patients not restarted on study drug/unknown
Time study drug restarted after CABG, %*
<7 days
7–14 days
>14 days
*Percentages calculated based on number of patients with available data
Study drug ≤7 days
before CABG
Ticagrelor
(n=632)
Clopidogrel
(n=629)
13.3
16.8
18.0
13.3
12.5
14.4
11.7
14.0
13.7
11.6
11.0
15.3
17.5
17.0
n=234
n=238
(n=398)
57.0
27.9
15.1
(n=391)
57.5
25.6
16.9
Co-medication (at study start)
Study drug ≤7 days
before CABG
Ticagrelor
(n=632)
Clopidogrel
(n=629)
Anti-thrombotic treatment in hospital, %
Aspirin before randomization
Aspirin after randomization
Unfractionated heparin
Low molecular weight heparin
Fondaparinux
Bivalirudin
Glycoprotein IIb/IIIa inhibitor
94.5
97.2
56.3
62.2
3.2
0.3
21.2
93.3
97.1
56.4
60.6
2.9
0.8
22.4
Other medication in hospital, %
Beta blocker
ACE inhibitor and/or ARB
Cholesterol-lowering (statins)
Calcium channel inhibitor
Diuretics
Proton pump inhibitor
91.5
82.4
96.8
28.6
58.5
54.6
89.5
84.6
97.5
30.0
58.7
59.8
Medication
ACE = angiotensin II-converting enzyme; ARB = angiotensin II receptor blocker
Time to first CABG surgery by treatment
(total PLATO population)
Study drug ≤7 days
before CABG
K-M estimated rate (%)
12
Clopidogrel
11.4
10.9
Ticagrelor
10
8
6
4
2
HR: 0.96 (95% CI = 0.87–1.05), p=0.36
0
0
No. at risk
Ticagrelor 9,235
Clopidogrel 9,186
1
2
7,289
7,320
3
4
5
6
7
8
Months from randomization
6,862
6,936
6,570
6,657
5,144
5,209
9
10
3,775
3,843
11
12
3,414
3,470
Primary endpoint: CV death, MI or stroke
14
Study drug ≤7 days
before CABG
Clopidogrel
13
13.1
12
K-M estimated rate (%)
11
10.6
10
Ticagrelor
9
8
7
6
5
4
3
2
1
HR: 0.84 (95% CI = 0.60–1.16), p=0.29
0
0
No. at risk
Ticagrelor 629
Clopidogrel 629
1
2
543
541
3
4
5
6
7
8
Months from CABG procedure
519
516
458
448
386
386
9
10
268
255
11
12
108
125
Primary and secondary efficacy
endpoints post-CABG
Characteristic
Ticagrelor Clopidogrel
(n=631)
(n=629)
Study drug ≤7 days
before CABG
Hazard Ratio (95% CI)
p-value
Primary endpoint
10.5
12.6
MI
5.9
5.6
CV death
4.0
7.5
Stroke
2.1
1.7
Non-hemorrhagic/
unknown stroke
2.1
1.6
Hemorrhagic stroke
0.0
0.2
All-cause mortality
4.6
9.2
Non-CV death
0.6
1.7
CV death + MI + stroke
0.84 (0.60, 1.16)
0.29
Secondary endpoints
1.06 (0.66, 1.68)
0.52 (0.32, 0.85)
0.009
1.17 (0.53, 2.62)
1.29 (0.57, 2.95)
0.49 (0.32, 0.77)
0.5
Ticagrelor better
Patients could have had more than one type of endpoint.
Event rate is number of events divided by n
1.0
0.70
0.54
0.002
0.35 (0.11, 1.11)
0.2
0.82
0.07
2.0
Clopidogrel better
CV death post-CABG
Study drug ≤7 days
before CABG
Clopidogrel
8
7.9
K-M estimated rate (%)
7
6
5
4
4.1
Ticagrelor
3
2
1
HR: 0.52 (95% CI = 0.32–0.85), p=0.009
0
0
No. at risk
Ticagrelor 629
Clopidogrel 629
1
2
583
565
3
4
5
6
7
8
Months from CABG procedure
557
539
491
472
415
404
9
10
291
269
11
12
119
130
All cause mortality post-CABG
Study drug ≤7 days
before CABG
Clopidogrel
10
9.7
9
K-M estimated rate (%)
8
7
6
5
4.7
Ticagrelor
4
3
2
1
HR: 0.49 (95% CI 0.32–0.77), p<0.01
0
0
No. at risk
Ticagrelor 629
Clopidogrel 629
1
2
583
565
3
4
557
539
5
6
7
Months
491
472
8
415
404
9
10
291
269
11
12
119
130
Safety: bleeding post-CABG
Characteristic
CABG-related bleeding
Study drug ≤7 days
before CABG
Ticagrelor Clopidogrel
(n=631)
(n=629)
Odds Ratio (95% CI)
p-value
Major bleeding
81.2
80.1
1.07 (0.80, 1.43)
0.67
Life-threatening/
fatal bleeding
43.7
42.6
1.04 (0.83, 1.31)
0.73
Fatal bleeding
0.8
1.0
All intracranial
bleeding post-CABG*
0.2
0.2
TIMI major bleeding
59.3
TIMI minor bleeding
GUSTO severe bleeding
0.83 (0.20, 3.28)
0.77
1.01 (0.06, 16.09)
1.00
57.6
1.08 (0.85, 1.36)
0.53
21.0
21.6
0.97 (0.73, 1.28)
0.84
10.6
12.2
0.85 (0.59, 1.22)
0.38
0.2
0.5
Ticagrelor better
All event rates are number of events divided by n
*Hazard ratio Kaplan-Meier estimates. Both CABG-related and
non-related
1.0
2.0
Clopidogrel better
Safety: bleeding post-CABG (cont’d)
Characteristic
Ticagrelor Clopidogrel
(n=631)
(n=629)
Study drug ≤7 days
before CABG
Hazard/Odds Ratio (95% CI)
p value
Hemoglobin decrease*
>50 g/L
38.1
36.2
1.08 (0.86, 1.37)
0.52
>30 g/L
69.9
67.6
1.12 (0.87, 1.43)
0.40
Major/life-threatening
CABG-related
bleeding resulting
in death within
7 days of CABG†
1.3
2.9
Re-operation
due to bleeding*
4.0
3.3
0.44 (0.19, 1.01)
0.05
1.19 (0.63, 2.27)
0.2
0.5
Ticagrelor better
*Odds ratio and p-value from Fisher’s exact test
†Hazard ratio
Event rate is number of events divided by n
1.0
2.0
Clopidogrel better
0.65
Treatment safety: transfusions post-CABG
Characteristic
Ticagrelor Clopidogrel
(n=631)
(n=629)
Study drug ≤7 days
before CABG
Hazard/Odds Ratio (95% CI)
p value
Transfusions within 7 days post-CABG
Any transfusion
55.2
55.8
0.98 (0.85, 1.14)
0.83
PRBC or whole blood*
52.7
51.2
1.03 (0.88, 1.20)
0.69
Platelets
15.3
17.3
0.88 (0.67, 1.16)
0.37
Fresh frozen plasma
25.2
24.0
1.05 (0.84, 1.31)
0.67
Transfusions post CABG-related bleeding†
>4 units blood
17.9
16.2
>5 units whole blood/
PRBC (2 days)
4.9
4.0
Chest tube output >2L
(24 hours)†
3.3
2.7
1.12 (0.83, 1.53)
1.25 (0.70, 2.23)
1.24 (0.61, 2.52)
0.2
0.5
Ticagrelor better
1.0
2.0
Clopidogrel better
*Median (range) units transfused within 7 days post-CABG: tic 3.0 (2.0–4.0) vs. clop 3.0 (2.0–4.0); p=0.86
†Odds ratio and p-value from Fisher’s exact test
0.45
0.49
0.62
CABG-related bleeding
Study drug ≤7 days
before CABG
Ticagrelor
Clopidogrel
100
K-M estimated rate (% per year)
90
NS
81.2
80.1
80
NS
70
59.3
60
57.6
50
40
NS
30
21.0
21.6
20
NS
10.6
12.2
NS
10
0.8
1.0
0
Major CABGrelated bleeding
CABG-related
TIMI major
bleeding
CABG-related
TIMI minor
bleeding
CABG-related
GUSTO severe
bleeding
CABG-related
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. New Eng J Med. 2007;357:2001–15;
NS = not significant
Limitations
Study drug ≤7 days
before CABG
• Retrospective analysis of a non-randomized subgroup of
patients requiring CABG
– selection bias, survivor bias or other confounders
• The formal adjudication of causes of deaths in the main trial
separated death from vascular and non-vascular cause, but a
further subcategorization was not performed
– a retrospective central review of the causes of post-CABG death
is currently ongoing
Conclusions
Study drug ≤7 days
before CABG
• In ACS patients undergoing CABG within 7 days after stopping
treatment with ticagrelor – a reversible, more intense P2Y12
receptor antagonist – is associated with
– substantially fewer deaths – both total and CV
– no change in the overall risk of CABG-related bleeding
In ACS patients undergoing CABG surgery, ticagrelor is a
more effective alternative to clopidogrel for the continuous
prevention of cardiovascular and total death without
an increase in major bleeding