cannon plato invasive

8/14/2019 Cannon Plato Invasive

1/21

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


2/21

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


3/21

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


4/21

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


5/21

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


6/21

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


7/21

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


8/21

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


9/21

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


10/21

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


11/21

Invasive

No. at risk

Clopidogrel

Ticagrelor

6,676

6,732

6,157

6,268

6,062

6,173

5,917


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


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


12/21

InvasiveAll-cause mortality

6

4

2

00 60 120 180 240 300 360

Clopidogrel

Ticagrelor


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


13/21

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


14/21

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


15/21

InvasivePrimary safety event: Major bleeding*

No. at risk

Clopidogrel

Ticagrelor

6,585

6,651

5,215

5,235

4,984

4,947

4,786


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


16/21

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


17/21

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


18/21

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


19/21

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


20/21

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)


21/21

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

cannon plato invasive

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